8-Phenylisoquinolines And Pharmaceutical Composition Used In Treatment For Sepsis

ABSTRACT

A compound is provided. The compound includes a formula of:

FIELD OF THE INVENTION

The present invention relates to a series of 8-phenylisoquinolinederivatives, and more particularly to a series of 8-phenylisoquinolinederivatives used in treatment for sepsis

BACKGROUND OF THE INVENTION

Sepsis syndrome is a serious whole-body inflammation disease caused bybacteria-released toxins into blood. This syndrome often causes bloodcoagulation of the patients, and they finally die of multiple organdysfunction syndromes. According to several epidemiological studies,rates of hospitalization for severe sepsis range from 50 to 300 casesper 100,000 in USA, and the mortality of severe sepsis in ICU rangesfrom 18% to 55%. The medical cost per patient was estimated fromUS$26,450 to US$39,100.

In Taiwan, the rate of severe sepsis incidence is 359 per 100,000, andthe mortality of severe sepsis is about 30%. The estimated cost forcaring a sepsis patient is 866-6505 USD. So far, the main management ofsepsis is symptoms relief and vital signs supports, such as usinganti-inflammation drugs, antibiotics, blood-vessel constriction drugsand intravenous drips.

Currently, the only one FDA-proved therapeutic agent for reducingmortality of severe sepsis patients and treating sepsis is Drotrecoginalfa (Xigris®). Xigris® is a recombinant human activated protein C byrecombinant genetic technology. The recombinant human activated proteinC could inhibit the activity of the Factor Va and Factor VIIIa, inhibitthe synthesis of the thrombin and inhibit the synthesis of plasminogenactivator inhibitor-1 (PAI-1) to regulate the coagulation reaction andpossess the features of anti-thrombus and fibrinolysis. However,according to several clinical researches, the benefit effects of Xigris®on reducing mortality of servere sepsis patients is still controversial,so new therapeutic agents for sepsis is still desired.

Serotonin (also called 5-hydroxytryptamine or 5-HT) is aneurotransmitter which could induce coagulation of platelets,contraction of coronary artery. 5-HT_(2A) receptor, which is one subtypeof the 5-HT receptor family and a G-protein coupled receptor.

The present 5-HT_(2A) receptor antagonists include sarpogrelate andketanserin. The method of treatment sepsis using 5-HT_(2A) receptorantagonists is still under research. In order to overcome the drawbacksin the prior art, a novel series of 8-phenylisoquinolines andpharmaceutical composition used in treatment for sepsis is provided.

SUMMARY OF THE INVENTION

In accordance with an aspect of the present invention, a compound isprovided. The compound includes a formula of:

In accordance with another aspect of the present invention, A compoundor a pharmaceutically acceptable salt thereof is provided. The compoundor a pharmaceutically acceptable salt thereof includes a formula of:

wherein R₁ is one selected from a group consisting of hydrogen, C₁₋₁₂linear chain alkyl group, C₁₋₁₂ branched chain alkyl group,(CH₂)_(n)(Hete)R₁₀R₁₁R₁₂ and (CH₂)_(n)ArR₁₀R₁₁R₁₂, wherein the n is aninteger from 1 to 6, Hete is a heterocyclic group, and R₁₀, R₁₁ and R₁₂are independently selected from a group consisting of hydrogen, halogroup, nitro group, amino group, cyano group, acetyl group, C₁₋₆ linearchain saturated alkyl group, C₁₋₆ linear chain saturated alkoxy groupand C₁₋₆ linear chain saturated haloalkyl group;

R₂ is one of a hydrogen and a C₁₋₆ linear chain saturated alkyl group;

R₃ is one of a hydroxyl group and a C₁₋₆ linear chain saturated alkoxygroup;

R₄ is one of a hydroxyl group and a C₁₋₆ linear chain saturated alkoxygroup; and

X₁, X₂, X₃, X₄ and X₅ are independently selected from a group consistingof hydrogen, halo group, nitro group, amino group, cyano group, acetylgroup, C₁₋₆ linear chain saturated alkyl group, C₁₋₆ branched chainsaturated alkyl group, C₁₋₆ linear chain saturated alkoxy group, C₁₋₆branched chain saturated alkoxy group, C₁₋₆ linear chain saturatedalkylthio group, C₁₋₆ branched chain saturated alkylthio group, C₁₋₆linear chain saturated haloalkyl group and C₁₋₆ branched chain saturatedhaloalkyl group.

In accordance with a further aspect of the present invention, apharmaceutical composition is provided. The pharmaceutical compositionis provided includes: a pharmaceutically acceptable carrier; and

-   -   a therapeutically effective amount of a compound having a        formula of:

-   -   wherein R₁ is one selected from a group consisting of hydrogen,        C₁₋₁₂ linear chain alkyl group, C₁₋₁₂ branched chain alkyl        group, (CH₂)_(n)(Hete)R₁₀R₁₁R₁₂ and (CH₂)_(n)ArR₁₀R₁₁R₁₂,        wherein the n is an integer from 1 to 6, Hete is a heterocyclic        group, and R₁₀, R₁₁ and R₁₂ are independently selected from a        group consisting of hydrogen, halo group, nitro group, amino        group, cyano group, acetyl group, C₁₋₆ linear chain saturated        alkyl group, C₁₋₆ linear chain saturated alkoxy group and C₁₋₆        linear chain saturated haloalkyl group;    -   R₂ is one of a hydrogen and a C₁₋₆ linear chain saturated alkyl        group;    -   R₃ is one of a hydroxyl group and a C₁₋₆ linear chain saturated        alkoxy group;    -   R₄ is one of a hydroxyl group and a C₁₋₆ linear chain saturated        alkoxy group; and    -   X₁, X₂, X₃, X₄ and X₅ are independently selected from a group        consisting of hydrogen, halo group, nitro group, amino group,        cyano group, acetyl group, C₁₋₆ linear chain saturated alkyl        group, C₁₋₆ branched chain saturated alkyl group, C₁₋₆ linear        chain saturated alkoxy group, C₁₋₆ branched chain saturated        alkoxy group, C₁₋₆ linear chain saturated alkylthio group, C₁₋₆        branched chain saturated alkylthio group, C₁₋₆ linear chain        saturated haloalkyl group and C₁₋₆ branched chain saturated        haloalkyl group.

The excipient or “pharmaceutically acceptable carrier or excipient” or“bioavailable carrier or excipient” includes solvent, dispersant,coating, antimicrobial agent, antifungal agent to preserve ordelay-absorbed agent and any other known compound to prepareformulation. In general, these carrier or excipient themselves do nothave activity of treating disease. The derivatives disclosed in thepresent invention in combination with pharmaceutically acceptablecarrier or excipient, preparing formulation do not cause adverse effect,allergy or other inappropriate reaction of animals or humans. Therefore,the derivatives disclosed in the present invention in combination withpharmaceutically acceptable carrier or excipient could be applied tohuman clinically. The formulation of the present invention compoundcould achieve therapeutic effect through intravenous injection, oraladministration, inhalation or through local administration of nose,rectum, vagina or hypoglottis. The 0.1 mg to 100 mg of an activeingredient per day is administrated for different disease of patients.

The carrier is different with different formulation. The composition forsterile injection could be suspended in sterile intravenous injectiondiluents or solvents, such as 1,3-butanediol. The acceptable carriercould be mannitol or water. In addition, the oil fixed or synthesizedmonoglyceride/diglyceride suspension medium are commonly used solvents.Fatty acids, such as oleic acid, olive oil, castor oil, glyceridederivatives, especially the polyoxyethylenated form could be preparedfor injection and natural pharmaceutically acceptable oil. These oilsolution or suspension include long-chain alcohol diluents, dispersant,carboxymethyl cellulose or similar dispersant. Other surfactants forcommon use include Tween, Spans, other similar emulsifier,pharmaceutically acceptable solid for pharmaceutical manufactureindustry, liquid, or other bioavailable enhancer for formulationdevelopment.

The composition for oral administration is adapted to oral acceptableformulation, wherein the types include capsule, lozenge, troche,emulsifier, liquid suspension, dispersant and solvent. The commoncarrier used for oral administration such as lozenge, for example, couldbe lactose, corn starch, lubricant, magnesium stearate as basicadditives. The diluents used for capsule include lactose, dry cornstarch. The preparation for liquid suspension or emulsifier formulationis to suspend or dissolve active ingredients with binding emulsifiers oroil interface of suspending agent. The sweetening agents, flavoringagent or coloring matter.

The aerosol sprayer for oral use or inhalation composition is preparedby known formulation technologies. For example, the composition isdissolved in physiological saline, added with benzyl alcohol, othersuitable preservative or absorbefacient to enhance bioavailableproperties. The composition of the present invention compound could alsobe prepared to suppository which is administrated through rectum orvagina.

The injections include hypodermic, peritoneal cavity, vein, muscle,joint cavity, intracranial, synovial fluid, intrathecal injection, aortainjection, thoracic injection, lesion injection or other suitableadministration technologies.

The above aspects and advantages of the present invention will becomeapparent to those ordinarily skilled in the art after reviewing thefollowing detailed descriptions and accompanying drawing.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the synthetic scheme 1 of novel derivatives of8-phenylisoquinoline;

FIG. 2 shows the synthetic scheme 2 of novel derivatives of8-phenylisoquinoline;

FIG. 3 shows the synthetic scheme 3 of novel derivatives of8-phenylisoquinoline;

FIG. 4 shows the synthetic scheme 4 of novel derivatives of8-phenylisoquinoline;

FIG. 5 shows the synthetic scheme 5 of novel derivatives of8-phenylisoquinoline;

FIG. 6 shows the synthetic scheme 6 of novel derivatives of8-phenylisoquinoline;

FIG. 7 shows the protective effects of post-treatment of multiple dosesof compound 116 on LPS induced endotoxaemia in the mice model;

FIG. 8 shows the protective effects of post-treatment of multiple dosesof compound 167 on LPS induced endotoxaemia in the mice model;

FIGS. 9 a-9 d show that compound 116 did not exert platelet activation,but inhibited 5-HT induced amplification of platelet aggregation; and

FIG. 10 shows that compound 116 inhibits serotonin induced ratde-endothelial thoracic descending aorta contraction.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention will now be described more specifically withreference to the following embodiments. It is to be noted that thefollowing descriptions of preferred embodiments of this invention arepresented herein for the purposes of illustration and description only;it is not intended to be exhaustive or to be limited to the precise formdisclosed.

The present invention provides a library of novel derivatives of8-phenylisoquinoline. The synthesis includes the following 6 schemes.

Scheme 1 (FIG. 1): Protection of the hydroxyl group in vanillin withbenzyl bromide yielded aldehyde 1 is shown in Scheme 1. Henry reactionbetween aldehyde 1 and nitromethane gave nitrostyrene 2. Reduction ofcompound 2 with lithium aluminum hydride in tetrahydrofuran (THF)afforded amine 3. The reaction of amine 3 with an excess amount ofmethyl formate provided formamide 4. Cyclization of amide 4 usingphosphorus oxychloride (POCl₃) via Bischler-Napieralski reactionobtained 3,4-dihydroisoquinoline 5. Alkylation of compound 5 withiodopropane followed by NaBH₄ reduction produced tetrahydroisoquinoline6 in high yield. Catalytic hydrogenation over Pd/C removed theprotective groups of 6 to afford 1,2,3,4-tetrahydroisoquinolin-7-ol 7 inquantitative yield. Treatment of compound 7 with Pb(OAc)₄ in acetic acidfollowed by acid-catalyzed aromatic substitution with1,3-dimethoxybenzene using trifluoroacetic acid (TFA) furnished8-phenyl-tetrahydroisoquinolin-7-ol 8.

Scheme 2 (FIG. 2): The 1-methyl-substituted8-phenyl-tetrahydroisoquinolin-7-ol derivatives were synthesizedstarting from amine 3. Treatment of 3 with an excess amount of methylacetate yielded acetamide 9, which was then converted to3,4-dihydroisoquinoline 10 using POCl₃. N-Alkylation of 10 with alkylhalides followed by NaBH₄ reduction obtained tetrahydroisoquinolines 11and 12. The benzyl protecting groups of 11 and 12 were then removed bycatalytic hydrogenation to provide phenols 13 and 14, respectively asshown in Scheme 2. Treatment of 13 and 14 with Pb(OAc)₄ in acetic acidfollowed by acid-catalyzed aromatic substitution with1,3-dimethoxybenzene using TFA afforded1-methyl-8-phenyl-tetrahydroisoquinolin-7-ols 15 and 16, respectively.

Scheme 3 (FIG. 3): The N-phenylethyl-substituted8-phenyl-tetrahydroisoquinolin-7-ol derivatives were synthesizedstarting from the commercially available7-hydroxy-6-methoxy-3,4-dihydroisoquinoline (20) as depicted in Scheme3. N-alkylation of compound 20 with phenylethyl bromide followed byNaBH₄ reduction provided amine 21. Treatment of phenethylamine 21 withPb(OAc)₄ followed by aromatic substitution with HBr produced8-bromo-tetrahydroisoquinoline 22. The desired target compounds 29-45were then synthesized from 22 with various substituted-arylboranes usingSuzuki coupling reaction condition in moderate yields.

Scheme 4 (FIG. 4): The N-substituted8-(2,4-dimethoxyphenyl)-tetrahydroisoquinolin-7-ols were also preparedstarting from the commercially available compound 20 as shown in Scheme4. Treatment of compound 20 with various halides followed by NaBH₄reduction yielded N-substituted tetrahydroisoquinolin-7-ols 61-76.Oxidation of compounds 61-76 with Pb(OAc)₄ in acetic acid followed byTFA-catalyzed aromatic substitution with 1,3-dimethoxybenzene affordedthe corresponding N-substituted8-(2,4-dimethoxyphenyl)-6-methoxy-tetrahydroisoquinolin-7-ols 101-125,respectively.

Scheme 5 (FIG. 5): Treatment of compound 20 with various 3-phenylpropylbromides followed by NaBH₄ reduction provided the correspondingN-3-phenylpropyl-substituted tetrahydroisoquinolin-7-ol derivatives 77and 78 as depicted in Scheme 5. Bromides 97 and 98 were obtained bytreatment of compounds 77 and 78 with Pb(OAc)₄ followed by aromaticsubstitution with HBr, respectively. Aryl coupling reaction of compounds97 and 98 under Suzuki reaction condition with varioussubstituted-arylboranes afforded the N-3-phenylpropyl-substituted6-methoxy-8-phenyl-tetrahydroisoquinolin-7-ols 141 and 142 in moderateyields, respectively.

Scheme 6 (FIG. 6): The N-phenylethyl-substituted6,7-dimethoxy-8-phenyl-tetrahydroisoquinoline derivatives 157-173 wereprepared using N-phenylethyl-substituted8-bromo-6-methoxy-tetrahydroisoquinolin-7-ols 60-96 as depicted inScheme 6. O-Methylation of phenols 60-96 with methyl iodide in thepresence of NaH gaves 6,7-dimethoxy-tetrahydroisoquinolines 150-154,respectively. Aryl coupling reaction of compounds 150-154 with varioussubstituted-arylboranes under Suzuki reaction condition furnished6,7-dimethoxy-8-phenyl-tetrahydroisoquinolines 157-173, respectively.

The specific synthesizing steps of the compounds from the above schemes1-6 are as follows:

Compound 7: A mixture of compound 5 (500 mg, 1.87 mmol), C₃H₇Br (0.51mL, 5.63 mmol), and 2-propanol (17 mL) was refluxed for 16 hours. Theresulting solution was concentrated and MeOH (25 mL) was added todissolve the residue. The solution was cooled in an ice-bath and thenNaBH₄ (167 mg, 4.41 mmol) was added slowly under N₂. The mixture wasstirred for another 10 minutes and then concentrated. The residue wastreated with H₂O and CHCl₃ (35 mL), and then the organic layer waswashed with brine, dried over MgSO₄, filtered, and evaporated. The cruderesidue was chromatographed (silica gel, EtOAc/n-hexane=1:2) to affordcompound 6 as a pale yellow solid (442 mg, 1.42 mmol, 76%), which wasused in the following reaction without further purification. A mixtureof compound 6 (431 mg, 1.38 mmol) and 10% Pd/C (160 mg) in EtOAc (8.5mL) was stirred under H₂ (1 atm) for 2 hours, and the catalyst wasremoved by filtration with the aid of Celite. The filtrate wasconcentrated and the crude residue was chromatographed (silica gel,MeOH/CH₂Cl₂=1:100) to obtain compound 7 as a pale solid (266 mg, 1.20mmol, 87%).

Compound 21: A mixture of compound 20 (100 mg, 0.56 mmol), 2-phenylethylbromide (311 mg, 1.68 mmol), and 2-propanol (3.5 mL) was refluxed for 15hours. The resulting solution was concentrated and MeOH (5 mL) was addedto dissolve the residue. The solution was cooled in an ice-bath and thenNaBH₄ (49 mg, 1.29 mmol) was added slowly under N₂. The mixture wasstirred for another 10 minutes and then concentrated. The residue wastreated with H₂O (20 mL) and CHCl₃ (20 mL), and then the organic layerwas washed with brine, dried over MgSO₄, filtered, and evaporated. Thecrude residue was chromatographed (silica gel, MeOH/CH₂Cl₂=1/100) toafford compound 21 as a white solid (146 mg, 0.52 mmol, 92%).

Compound 30: To a solution of C₁₈H₂₀BrNO₂ (50 mg, 0.14 mmol) in2-propanol (2.0 mL) in a 10-mL thick walled Pyrex reaction vessel,4-methoxyphenylboronic acid (26 mg, 0.19 mmol) was added. After stirringfor 30 min, Pd(OAc)₂ (1.3 mg, 0.006 mmol), PPh₃ (4.7 mg, 0.02 mmol), 2 MNa₂CO_(3(aq)) (0.09 mL, 0.17 mmol), and H₂O (0.1 mL) were added. Thenthe mixture was heated at 140° C. for 10 min in a microwave synthesizer,and H₂O (0.35 mL) was added before cooling to room temperature. Theresulting solution was diluted with H₂O (5 mL) and extracted with EtOAc(5 mL). The organic layer was washed with 5% NaHCO_(3(aq)) and brine.The organic solution was treated with Darco G-60 (100 mg) and stirred atroom temperature for 30 min, and then dried over MgSO₄, filtered (thesintered glass funnel was charged with Celite to a depth of 1 cm andFlorisil was spread evenly on the top of the Celite), and evaporated.The crude residue was chromatographed (silica gel, EtOAc/n-hexane=2/1)to afford an orange oil (40 mg, 0.10 mmol, 73%).

Compounds 29 and 31-40: Table 1 is a parameter table. “Parameter 1” isadded into the reaction vessel for microwave-assisted heating anddissolved with “parameter 2” mL 2-propanol. The appearance of solutionis “parameter 3” and the reagent “parameter 4” is added thereinto, andstirred for “parameter 5” minutes. The appearance of resulting solutionis “parameter 6”. The Pd(OAc)₂ “parameter 7”, PPh₃ “parameter 8”, 2 MNa₂CO₃(aq) “parameter 9” and “parameter 10” mL H₂O are added and heated“parameter 11”. Before the temperature of the solution is decreased,“parameter 12” mL H₂O is added, stirred in the air until reaching roomtemperature, diluted with “parameter 13” mL EtOAc, and extracted with“parameter 14” mL H₂O. The organic layer is washed with 5% NaHCO₃(aq),washed with brine, added in “parameter 15” mg Darco G-60, stirred for“parameter 16” minutes, added in MgSO₄ for drying, stirred for“parameter 17” minutes, filtered by the sintered glass funnel coveredwith about 1 cm of Celite and a thin layer of Florisil, concentrated fordrying and purified by flash column chromatography (silica gel,“parameter 18”) to obtain “parameter 19”.

TABLE 1 The parameter table for the synthesis of compounds 29 and 31-4029 31 32 33 34 35 1 2- C₁₈H₂₀BrNO₂ C₁₈H₂₀BrNO₂ phenylboronic2-(methylthio)phenyl- 4-(methylthio)phenyl- methoxyphenylboronic (100mg, (150 mg, 0.41 mmol) acid (43 mg, boronic acid (59 mg, boronic acid(125 mg, acid (65 mg, 0.43 mmol) 0.28 mmol) 0.35 mmol) 0.35 mmol) 0.74mmol) 2 2.0 2.0 2.0 2.0 2.0 3.0 3 transparent — — — transparenttransparent colorless light yellow colorless 4 C₁₈H₂₀BrNO₂3-methoxyphenyl- 3,4,5-trimethoxy- C₁₈H₂₀BrNO₂ C₁₈H₂₀BrNO₂ C₁₈H₂₀BrNO₂(100 mg, boronic acid (62 mg, benzeneboronic (100 mg, 0.28 mmol) (100mg, 0.28 mmol) (150 mg, 0.41 mmol) 0.28 mmol) 0.41 mmol) acid (106 mg,0.50 mmol) 5 30 30 10 30 30 25 6 turbid dirt turbid beige turbid beigeturbid beige turbid orange turbid white yellow white white white yellow7 2.5 mg, 0.011 mmol 1.2 mg, 0.005 mmol 1.9 mg, 0.008 mmol 1.9 mg, 0.008mmol 2.2 mg, 0.01 mmol 2.7 mg, 0.01 mmol 8 5.6 mg, 0.021 mmol 3.1 mg,0.01 mmol 5.2 mg, 0.02 mmol 5.4 mg, 0.02 mmol 7.0 mg, 0.027 mmol 10 mg,0.04 mmol 9 0.18 mL, 0.18 mL, 0.27 mL, 0.50 mmol 0.18 mL, 0.34 mmol 0.17mL, 0.34 mmol 0.25 mL, 0.49 mmol 0.34 mmol 0.34 mmol 10 0.2 0.2 0.3 0.20.2 0.3 11 120° C. for 20 120° C. for 10 120° C. for 10 120° C. for 10140° C. for 20 140° C. for 20 minutes minutes minutes minutes minutesminutes 12 0.7 0.7 1.0 0.7 0.7 1.1 13 10 5 10 10 20 20 14 10 0 0 0 10 2015 100 100 150 117 106 180 16 5 30 5 15 20 10 17 10 30 10 10 10 10 18EA/n-hexane = EA/n-hexane = EA/n-hexane = EA/n-hexane = EA/n-hexane =EA/n-hexane = 1/1 1/1 1/1 1/3 1/2 1/2 19 orange light yellow lightyellow oil light yellow orange oil orange oil yellow oil oil productsproducts (102 mg, oil products products (66 mg, products (148 mg,products (106 mg, (97 mg, 0.23 mmol, 0.23 mmol, (90 mg, 0.25 mmol, 0.16mmol, 0.37 mmol, 0.27 mmol, 83%) 55%) 89%) 58%) 89%) 97%) 36 37 38 39 401 3,4-(methylenedioxy)benzene 2-cyanophenylboronic acid2-nitrophenylboronic acid 2-chlorophenylboronic acid2-acetylphenylboronic acid boronic acid (74 mg, 0.50 mmol) (124 mg, 0.74mmol) (77 mg, 0.49 mmol) (80 mg, 0.49 mmol) (86 mg, 0.52 mmol) 2 3.0 3.03.0 3.0 3.0 3 transparent transparent transparent transparent turbidwhite light orange light yellow light yellow colorless 4 C₁₈H₂₀BrNO₂C₁₈H₂₀BrNO₂ C₁₈H₂₀BrNO₂ C₁₈H₂₀BrNO₂ C₁₈H₂₀BrNO₂ (150 mg, (151 mg, (152mg, 0.42 mmol) (150 mg, 0.41 mmol) (149 mg, 0.41 mmol) 0.41 mmol) 0.42mmol) 5 30 35 30 25 30 6 turbid beige turbid white turbid light turbidbeige turbid beige white yellow white yellow 7 3.0 mg, 0.01 mmol 3.0 mg,0.01 mmol 4 mg, 0.018 mmol 3.0 mg, 0.01 mmol 3.0 mg, 0.012 mmol 8 11 mg,0.04 mmol 10 mg, 0.037 mmol 16 mg, 0.06 mmol 11 mg, 0.042 mmol 10 mg,0.037 mmol 9 0.25 mL, 0.25 mL, 0.37 mL, 0.74 mmol 0.25 mL, 0.49 mmol0.25 mL, 0.50 mmol 0.49 mmol 0.49 mmol 10 0.3 0.3 0.3 0.3 0.3 11 140° C.for 20 140° C. for 20 120° C. for 20 140° C. for 20 140° C. for 20minutes minutes minutes minutes minutes 12 1.1 1.1 1.1 1.1 1.1 13 20 2020 20 20 14 20 20 20 20 20 15 197 195 176 160 150 16 10 10 10 10 10 1710 10 10 10 10 18 EA/n-hexane = EA/n-hexane = EA/n-hexane = EA/n-hexane= EA/n-hexane = 1/3 1/3 1/2 1/2 1/2 19 white solid light yellow lightyellow oil light yellow white solid products (134 mg, oil productsproducts (20 mg, oil products products (40 mg, 0.33 mmol, (33 mg, 0.09mmol, 0.05 mmol, (105 mg, 0.27 mmol, 0.10 mmol, 81%) 20%) 12%) 65%) 24%)

Compound 44: To a solution of C₁₈H₂₀BrNO₂ (100 mg, 0.28 mmol) in2-propanol (1.5 mL) in a 10-mL thick walled Pyrex reaction vessel,3,5-dimethoxybenzeneboronic acid (62 mg, 0.34 mmol) was added. Afterstirring for 30 min, Pd(OAc)₂ (2.2 mg, 0.01 mmol), PPh₃ (8.0 mg, 0.03mmol), 2 M Na₂CO_(3(aq)) (0.17 mL, 0.34 mmol), and H₂O (0.7 mL) wereadded. Then the mixture was heated at 140° C. for 10 min in a microwavesynthesizer, and H₂O (0.35 mL) was added before cooling to roomtemperature. The resulting solution was diluted with H₂O (10 mL) andextracted with EtOAc (10 mL). The organic layer was washed with 5%NaHCO_(3(aq)) (10 mL) and brine. The organic solution was treated withDarco G-60 (100 mg) and stirred at room temperature for 30 min, and thendried over MgSO₄, filtered (the sintered glass funnel was charged withCelite to a depth of 1 cm and Florisil was spread evenly on the top ofthe Celite), and evaporated. The crude residue was chromatographed(silica gel, EtOAc/n-hexane=1/1) to afford a yellow oil (76 mg, 0.18mmol, 65%).

Compound 45: To a solution of C₁₈H₂₀BrNO₂ (100 mg, 0.28 mmol) in2-propanol (2.0 mL) in a 10-mL thick walled Pyrex reaction vessel,2,3-dimethoxyphenylboronic acid (62 mg, 0.34 mmol) was added. Afterstirring for 30 min, Pd(OAc)₂ (2.0 mg, 0.009 mmol), PPh₃ (3.7 mg, 0.014mmol), 2 M Na₂CO_(3(aq)) (0.18 mL, 0.36 mmol), and H₂O (0.2 mL) wereadded. Then the mixture was heated at 120° C. for 10 min in a microwavesynthesizer, and H₂O (0.7 mL) was added before cooling to roomtemperature. The resulting solution was diluted with H₂O (5 mL) andextracted with EtOAc (5 mL). The organic layer was washed with 5%NaHCO_(3(aq)) (5 mL) and brine. The organic solution was treated withDarco G-60 (100 mg) and stirred at room temperature for 30 min, and thendried over MgSO₄, filtered (the sintered glass funnel was charged withCelite to a depth of 1 cm and Florisil was spread evenly on the top ofthe Celite), and evaporated. The crude residue was chromatographed(silica gel, EtOAc/n-hexane=1/1) to afford a yellow oil (82 mg, 0.20mmol, 71%).

Compounds 60, 85 and 95-98: Table 2 is a parameter table. The startingmaterial “parameter 1” is added into a reaction flask at roomtemperature under N₂, and “parameter 2” mL HOAc is added thereinto. ThePb(OAc)₄ “parameter 3” is added, and then the solution is “parameter 4”,poured into the conical flask and added with “parameter 5” mL Na₂CO₃(sat) slowly. The pH of the aqueous layer is alkaline (pH=“parameter6”). The solids produced in neutralization is filtered. The filter cakeis washed with CH₂Cl₂. The filtrate is extracted with “parameter 7” mLCH₂Cl₂. The organic layer is washed with brine, added with MgSO₄ fordrying, stirred for 5 minutes, filtered with the sintered glass funneland concentrated for drying to obtain “parameter 8” product. The crudeproduct was used in the following reaction without further purification.

The solution which is added in HBr “parameter 9” in the room temperatureair and the appearance of the solution is “parameter 10”. After stirringfor “parameter 11” hours, “parameter 12” mL Na₂CO₃ (sat) and “parameter13” mL CH₂Cl₂ are added slowly to the solution. The pH of the aqueouslayer is alkaline (pH=“parameter 14”), and then the “parameter 15” mLCH₂Cl₂ and “parameter 16” mL H₂O are added for extraction. The organiclayer is washed with brine, added with MgSO₄ for drying, stirred for 5minutes, filtered with the sintered glass funnel and concentrated fordrying to obtain crude product “parameter 17” mg. The “parameter 19” isafforded after flash column chromatography (silica gel, “parameter 18”).

TABLE 2 The parameter table for the synthesis of compounds 60, 85 and95-98 60 85 95 96 97 98 1 C₁₈H₂₁NO₂ C₁₈H₂₀N₂O₄ C₁₈H₂₀ClNO₂ C₁₈H₂₀FNO₂C₁₉H₂₂N₂O₄ C₁₉H₂₂N₂O₄ (351 mg, 1.24 mmol) (503 mg, 1.53 mmol) (1000 mg,(1002 mg, (320 mg, 0.93 mmol) (285 mg, 0.83 mmol) 3.15 mmol) 3.32 mmol)2 6.2 7.6 15.5 16.5 4.7 4.2 mL 3 830 mg, 1.87 mmol 1034 mg, 2.33 mmol2101 mg, 4.74 mmol 2262 mg, 5.10 mmol 636 mg, 1.43 mmol 562 mg, 1.27mmol 4 deep red transparent transparent transparent red brown tranparentred coffee color red coffee deep red burgundy red brown color brown 5 4060 100 130 25 25 6 8-9 8-9 8-9 8-9 8-9 8-9 7 50 80 100 130 40 40 8 deeporange red brown red brown red brown deep orange brown oil red solid(282 mg, solid (498 mg, solid (1089 mg, solid (1088 mg, red solid (303mg, (263 mg, 0.66 mmol) 0.83 mmol) 1.29 mmol) 2.91 mmol) 3.04 mmol) 0.76mmol) 9 6 mL, 48% wt 10 mL, 48% 15 mL, 48% 15 mL, 48% 5 mL, 48% wt 5 mL,48% wt wt wt wt 10 turbid yellow turbid orange turbid orange turbidorange turbid orange turbid orange 11 3 2 1.5 1.5 1 0.5 12 35 70 100 10035 35 13 20 50 50 50 20 20 14 8-9 8-9 9-10 9-10 8-9 8-9 15 15 50 80 6020 50 16 0 30 30 10 0 0 17 344 433 1013 973 225 195 18 EA/n-hexane =EA/n-hexane = MeOH/CH₂Cl₂ = EA/n-hexane = MeOH/CH₂Cl₂ = MeOH/CH₂Cl₂ =1/2 1/1 1/100 1/3 1/100 1/90 19 beige white yellow solid white solidwhite solid orange yellow orange yellow solid products products (363 mg,products (747 mg, products (752 mg, oil products oil products (260 mg,0.72 mmol, 0.89 mmol, 1.88 mmol, 1.98 mmol, (179 mg, 0.42 mmol, (170 mg,0.40 mmol, 58%) 59%) 60%) 60%) 46%) 49%)

Compounds 63-67, 67-70 and 74-78: Table 3 is a parameter table. Thestarting material “parameter 1” is added into a flask at roomtemperature under N₂, and then the “parameter 2” mL IPA and “parameter3” are added thereinto. The starting material is dissolved at “parameter4” ° C. The appearances of reaction solution are “parameter 5” and“parameter 7” in about “parameter 6” minutes, and then the solution isheated at 110˜120° C. for “parameter 8” hours and concentrated in roomtemperature. The “parameter 9” mL MeOH is added and the resultingmixture is stirred for “parameter 10” minutes. To the solution which is“parameter 11” in a ice-bath, is added NaBH₄(s) “parameter 12” slowlyunder N₂ and stirred for “parameter 13” minutes. The solution which is“parameter 14” is added with “parameter 15” mL H₂O and extracted with“parameter 16” mL CHCl₃. The organic layer is added with MgSO₄ fordrying, stirred for “parameter 17” minutes, filtered, and concentratedto obtain “parameter 18”. The “parameter 20” is afforded after flashcolumn chromatography (silica gel, “parameter 19”).

TABLE 3 The parameter table for the synthesis of compounds 63-67, 67-70and 74-78 63 64 65 66 67 69 1 C₁₀H₁₁NO₂ C₁₀H₁₁NO₂ C₁₀H₁₁NO₂ C₁₀H₁₁NO₂C₁₀H₁₁NO₂ C₁₀H₁₁NO₂ (20, 300 mg, (20, 300 mg, (20, 1001 mg, (20, 301 mg,(20, 300 mg, (20, 300 mg, 1.69 mmol) 1.69 mmol) 5.65 mmol) 1.70 mmol)1.69 mmol) 1.69 mmol) 2 10 10 35 14 10 10 3 C₈H₈NO₂Br C₈H₈NO₂BrC₈H₈NO₂Br 4-chlorophenethyl C₈H₇BrCl₂ C₈H₈Br₂ (1127 mg, (866 mg, 3.76mmol) (3810 mg, bromide (1.00 g, 3.94 mmol) (1.00 g, 3.79 mmol) 4.89mmol) 16.56 mmol) (1115 mg, 5.08 mmol) 4 60 75 — 80 80 80 5 transparenttransparent — transparent transparent transparent light yellow lightyellow yellow yellow yellow 6 30 10 — 120 120 90 7 turbid turbid yellowtransparent turbid yellow turbid yellow turbid yellow yellow orangeyellow 8 18 16 17 24 25 19 9 15 15 35 15 15 15 10 10 10 10 10 10 10 11turbid turbid yellow — transparent transparent transparent yellow yellowyellow yellow 12 264 mg, 206 mg, 3.39 mmol 853 mg, 22.53 mmol 576 mg,15.2 mmol 257 mg, 6.78 mmol 270 mg, 7.14 mmol 6.97 mmol 13 20 20 10 2020 20 14 turbid turbid orange — opaque orange opaque opaque yelloworange orange 15 30 0 0 30 30 30 16 30 30 100 30 30 30 17 5 5 5 5 5 5 18orange solid orange solid — orange solid orange solid orange solid crudecrude produts crude produts crude produts crude produts produts 19MeOH/CH₂Cl₂ = MeOH/CH₂Cl₂ = MeOH/CH₂Cl₂ = MeOH/CH₂Cl₂ = MeOH/CH₂Cl₂ =MeOH/CH₂Cl₂ = 1/60 1/60 1/80 1/90 1/100 1/100 20 canary white solidbeige yellow white solid yellow solid white solid yellow solid products(541 mg, solid products products (448 mg, products (442 mg, productsproducts 1.65 mmol, (1558 mg, 1.41 mmol, 1.26 mmol, (626 mg, (439 mg,97%) 4.74 mmol, 81%) 74%) 1.73 mmol, 1.34 mmol, 84%) 102%) 79%) 70 74 7576 77 78 1 C₁₀H₁₁NO₂ C₁₀H₁₁NO₂ C₁₀H₁₁NO₂ C₁₀H₁₁NO₂ C₁₀H₁₁NO₂ C₁₀H₁₁NO₂(20, 301 mg, (20, 300 mg, (20, 1002 mg, (20, 1000 mg, (20, 300 mg, (20,300 mg, 1.70 mmol) 1.69 mmol) 5.64 mmol) 5.64 mmol) 1.69 mmol) 1.69mmol) 2 10 10 35 35 10 10 3 C₁₀H₁₃O₂Br C₁₀H₁₃O₂Br 2-chlorophenethyl2-fluorophenethyl C₉H₁₀BrNO₂ C₉H₁₀BrNO₂ (1.0 g, 4.65 mmol) (1.0 g, 4.08mmol) bromide bromide (1215 mg, (989 mg, (3716 mg, (3438 mg, 4.98 mmol)4.05 mmol) 16.93 mmol) 16.93 mmol) 4 70 80 80 80 88 75 5 transparenttransparent transparent transparent transparent transparent light yelloworange yellow yellow orange white white 6 120 120 — — 210 60 7 turbidturbid yellow — — turbid yellow turbid yellow yellow 8 19 18 17 18 19.519.5 9 15 15 35 35 15 15 10 — — 10 10 10 10 11 transparent transparentturbid yellow transparent turbid yellow turbid yellow yellow orangeyellow light brown 12 272 mg, 270 mg, 7.13 mmol 825 mg, 21.8 mmol 836mg, 22.1 mmol 266 mg, 7.03 mmol 271 mg, 7.16 mmol 7.17 mmol 13 20 20 2020 20 20 14 transparent transparent opaque pinky opaque pinkytransparent transparent orange orange orange orange brown light orange15 30 30 100 100 30 30 16 30 30 100 100 30 30 17 5 5 5 5 5 5 18 orangesolid orange yellow light orange light orange orange oil orange oilproducts solid products solid products solid products products products19 MeOH/CH₂Cl₂ = MeOH/CH₂Cl₂ = MeOH/CH₂Cl₂ = MeOH/CH₂Cl₂ = MeOH/CH₂Cl₂ =MeOH/CH₂Cl₂ = 1/100 1/60 1/90 1/90 1/90 1/90 20 white solid beige whitewhite solid white solid yellow oil yellow oil products solid productsproducts (1601 mg, products products (503 mg, products (504 mg, 452 mg,1.32 mmol, 5.04 mmol, (1501 mg, 1.47 mmol, (492 mg, 1.61 mmol, 78%) 89%)4.98 mmol, 87%) 1.44 mmol, 95%) 88%) 85%)

Compound 68: A mixture of C₁₀H₁₁NO₂ (300 mg, 1.69 mmol), C₈H₈Br₂ (1.00g, 3.79 mmol), and 2-propanol (10 mL) was heated to reflux for 23 h. Theresulting solution was cooled to room temperature, and evaporated. Thecrude was dissolved in MeOH (15 mL), cooled to 0° C. in ice-bath, andthen NaBH₄ (420 mg, 11.1 mmol) was added in portions under N₂. Themixture was stirred for another 20 min and then concentrated. Theresidue was treated with CHCl₃ (30 mL) and H₂O (30 mL) and then theorganic layer was dried over MgSO₄, filtered and evaporated. Thepurification is performed by the precipitation method. The crude productis dissolved with 5 mL of EtOAc, and then the product is precipitateswith 10 mL of n-hexane to afford a beige solid (620 mg, 1.71 mmol).

Compound 121: To a solution of C₁₉H₂₃NO₂ (250 mg, 0.84 mmol) in HOAc(4.2 mL), Pb(OAc)₄ (579 mg, 1.31 mmol) was added and the mixture wasstirred at room temperature under N₂ for 15 min. The reaction mixturewas diluted with CH₂Cl₂ and Na₂CO_(3(sat)) (20 mL) was added slowly. Thesolids formed in neutralization were removed by filtration and washedwith CH₂Cl₂. The combined filtrate was extracted with CH₂Cl₂ (35 mL),and then the organic layer was washed with brine, dried over MgSO₄,filtered, and evaporated to afford a brown oil (480 mg, 1.35 mmol),which was used in the following reaction without further purification.To a solution of the crude oil in CH₂Cl₂ (17 mL), 1,3-dimethoxybenzene(0.17 mL, 1.3 mmol) and trifluoroacetic acid (0.84 mL) were added. Theresulting mixture was stirred at room temperature for 30 min, and thenNa₂CO_(3(sat)) (20 mL) was added slowly. The resulting solution wasextracted with CH₂Cl₂ (18 mL) and then the organic layer was washedbrine, dried over MgSO₄, filtered, and evaporated. The crude residue waschromatographed (silica gel, MeOH/CH₂Cl₂=1/10) to afford a red-brown oil(214 mg, 0.49 mmol, 59%).

Compounds 105-110, 114-116, 120, 122, 123 and 125: Table 4 is aparameter table. The starting material “parameter 1” is added into theflask at room temperature under N₂ and dissolved with “parameter 2” mLHOAc. The solution which is “parameter 3” is added with Pb(OAc)₄“parameter 4”, and then the resulting solution which is “parameter 5” isstirred for “parameter 6” minutes, poured into the 125 mL conical flask,stirred and added slowly with “parameter 7” mL Na₂CO_(3(sat)). The pH ofthe aqueous layer is alkaline (pH=8-9). The solid produced byneutralization is filtered and washed with CH₂Cl₂. The filtrate isextracted with “parameter 8” mL CH₂Cl₂. The organic layer is washed withbrine, added with MgSO₄ for drying, stirred for 5 minutes, filtered, andconcentrated to afford “parameter 9”. The crude product is used in thefollowing reaction without further purification.

The crude product is dissolved with “parameter 10” mL CH₂Cl₂ at roomtemperature under N₂. The solution which is “parameter 11” is added with1,3-dimethoxybenzene “parameter 12” and trifluoroacetic acid “parameter13”. The color of the solution turns into “parameter 14”. After thesolution is stirred for “parameter 15” minutes, “parameter 16” mLNa₂CO_(3(sat)) is added slowly. The pH of the aqueous layer is alkaline(pH=8-9), and “parameter 17” mL CH₂Cl₂ is added for extraction. Theorganic layer is washed with brine, added with MgSO₄ for drying, stirredfor 5 minutes, filtered, and concentrated to obtain “parameter 18” mgcrude product. The “parameter 20” is afforded after flash columnchromatography (silica gel, “parameter 19”).

TABLE 4 The parameter table for the synthesis of compounds 105-110,114-116, 120, 122, 123 and 125 105 106 107 108 109 1 C₁₈H₂₀N₂O₄C₁₈H₂₀ClNO₂ C₁₈H₁₉Cl₂NO₂ (250 mg, C₁₈H₂₀BrNO₂ C₁₈H₂₀BrNO₂ (250 mg, (160mg, 0.50 mmol 0.71 mmol) (250 mg, 0.69 mmol) (250 mg, 0.69 mmol) 0.76mmol) 2   3.8   2.5   3.6   3.5   3.6 3 transparent transparenttransparent light transparent light transparent light light yellow lightyellow green yellow green 4 509 mg, 337 mg, 0.76 mmol 473 mg, 1.07 mmol459 mg, 1.04 mmol 470 mg, 1.06 mmol 1.15 mmol 5 transparent deep coffeered black transparent transparent red brown color coffee color coffeecolor 6 15 60 27 15 15 7 25 20 25 40 25 8 40 40 50 35 9 red coffeecoffee color oil red coffe color oil deep coffee red coffee color coloroil products (218 mg, products (291 mg, color oil oil products products0.58 mmol) 0.71 mmol) products (214 mg, (262 mg, 0.62 mmol) (240 mg,0.51 mmol) 0.62 mmol) 10 15 12 14 10 13 11 transparent transparent redtransparent red transparent red transparent red deep red coffee colorcoffee color coffee color coffee color brown 12 0.14 mL, 0.11 mL, 0.87mmol 0.14 mL, 1.06 mmol 0.10 mL, 0.77 mmol 0.12 mL, 0.93 mmol 1.1 mmol13 0.73 mL 0.58 mL 0.71 mL 0.51 mL 0.62 mL 14 transparent transparentred transparent red transparent red transparent red deep black coffeebrown coffee brown to coffee brown to coffee brown to tea color to totransparent transparent light transparent light transparent lighttransparent light coffee coffee color coffee color coffee color teacolor color 15 30 60 30 30 70 16 25 10 20 30 15 17 20 23 26 30 27 18480  327  490  325  342  19 EA/n-hexane = MeOH/CH₂Cl₂/ MeOH/CH₂Cl₂/NH₄OH= MeOH/CH₂Cl₂/ EtOAc/n-hexane = 1/1 NH₄OH = 1/100/0.1 NH₄OH = 1/21/100/0.1 1/100/0.1 20 light orange coffee color oil coffee color oilred coffee color light brown oil yellow solid products (130 mg, products(152 mg, oil products (39 mg, products (80 mg, products 0.29 mmol, 0.31mmol, 44%) 0.11 mmol, 0.18 mmol, (151 mg, 57%) 11%) 26%) 0.33 mmol, 43%)110 114 115 116 120 1 C₁₉H₂₃NO₃ C₁₉H₂₃NO₂ C₁₈H₂₀ClNO₂ (250 mg,C₁₈H₂₀FNO₂ C₁₉H₂₃NO₃ (250 mg, (250 mg, (250 mg, 0.73 mmol) 0.79 mmol)(251 mg, 0.83 mmol) 0.798 mmol) 0.80 mmol) 2  4   3.7  4   4.2  4 3transparent transparent transparent light light orange light yellowlight yellow light yellow orange yellow yellow 4 569 mg, 505 mg, 1.14mmol 570 mg, 1.29 mmol 605 mg, 1.36 mmol 532 mg, 1.20 mmol 1.28 mmol 5transparent transparent red translucent red translucent red deep coffeered coffee coffee color coffee color coffee color color color 6 15 15 1515 15 7 25 30 25 25 25 8 40 35 35 35 35 9 red coffee red coffee redcoffee color oil red coffee color red coffee color color oil color oilproducts (300 mg, oil products oil products products products (253 mg,0.80 mmol) (285 mg, 0.79 mmol) (290 mg, 0.781 mmol) (243 mg, 0.63 mmol)0.65 mmol) 10 13 13 16 16 16 11 transparent coffee color transparent redtransparent red transparent red red coffee coffee color coffee colorcoffee color color 12 0.13 mL, 0.13 mL, 0.95 mmol 0.16 mL, 1.2 mmol 0.16mL, 1.2 mmol 0.15 mL, 1.2 mmol 0.98 mmol 13 0.65 mL 0.63 mL 0.79 mL 0.79mL 0.78 mL 14 transparent coffee color to transparent red transparentred transparent red red coffee light coffee coffee color to coffee colorto coffee color to color to color transparent light transparent lighttransparent transparent coffee color coffee color coffee color lightcoffee color 15 30 30 30 30 30 16 20 20 25 20 25 17 22 22 19 19 19 18450  433  480  417  560  19 EA/n-hexane = MeOH/CH₂Cl₂ = EA/n-hexane =1/2 MeOH/CH₂Cl₂/ MeOH/CH₂Cl₂/ 1/1 1/100 NH₄OH = NH₄OH = 1/100/0.11/100/0.1 20 light brown red coffee orange solid light orange coffeecolor oil oil products color oil products (128 mg, yellow solid products(162 mg, (217 mg, products (129 mg, 0.28 mmol, 36%) products (126 mg,0.36 mmol, 0.48 mmol, 0.26 mmol, 0.29 mmol, 45%) 60%) 36%) 35%) 122 123125 1 C₁₈H₂₀ClNO₂ C₁₉H₂₃NO₃ C₁₉H₂₃NO₂ (251 mg, (250 mg, (250 mg, 0.80mmol) 0.84 mmol) 0.79 mmol) 2   4.2  4   4.3 3 transparent transparenttransparent light orange orange yellow orange yellow yellow 4 540 mg,578 mg, 1.30 mmol 580 mg, 1.31 mmol 1.22 mmol) 5 deep coffee deep coffeetransparent red color color coffee color 6 17 15 15 7 25 25 35 8 35 3535 9 red coffee deep red coffee red coffee color oil color oil color oilproducts (283 mg, products products (290 mg, 0.80 mmol) (286 mg, 0.78mmol) 0.76 mmol) 10 13 16 16 11 transparent transparent transparent redred coffee deep red coffee coffee color color color 12 0.15 mL, 0.15 mL,1.2 mmol 0.16 mL, 1.2 mmol 1.1 mmol 13 0.76 mL 0.78 m 0.8 mL 14transparent transparent transparent deep red coffee deep red coffee redcoffee color to color to color to deep transparent light transparentcoffee color coffee color coffee color 15 33 30 30 16 25 25 25 17 22 1919 18 430  430  506  19 EA/n-hexane = EA/n-hexane = MeOH/CH₂Cl₂ = 1/11/1 1/200 20 orange light brown oil light orange yellow yellow solidproducts (140 mg, solid products (135 mg, products 0.31 mmol, 0.31 mmol,(151 mg, 39%) 37%) 0.33 mmol, 42%)

Compounds 141 and 142: Table 5 is a parameter table. “Parameter 1” and2-methoxyphenylboronic acid (46 mg, 0.30 mmol) are added into thereaction vessel for microwave-assisted heating and dissolved with2-propanol (2 mL), and stirred for 30 minutes. Pd(OAc)₂ “parameter 2”,PPh₃ “parameter 3”, 2 M Na₂CO_(3(aq)) (0.14 mL, 0.28 mmol), and H₂O (0.2mL) are added and the mixture is heated at 120° C. for 20 minutes usingmicrowave synthesizer. Before the temperature of the solution isdecreased, the solution us added H₂O (0.7 mL), stirred in the air untilreaching room temperature, diluted with 10 mL of EtOAc, and extractedwith 10 mL of H₂O. The organic layer is washed with 5% NaHCO_(3(aq)),washed with brine, added in “parameter 4” mg Darco G-60, stirred for 10minutes, added in MgSO₄ for drying, stirred for 10 minutes, filtered bythe sintered glass funnel covered with about 1 cm of Celite and a thinlayer of Florisil, concentrated. The crude product is purified by flashcolumn chromatography (silica gel, “parameter 5”) to obtain a yellow oil“parameter 6”. Free base “parameter 7” is dissolved in CH₂Cl₂, and thena solution of HCl in CH₂Cl₂ is added until pH=1. The resulting mixtureis concentrated to obtain hydrochloride salt “parameter 8”.

TABLE 5 The parameter table for the synthesis of compounds 141 and 142141 142 1 103 mg, 0.24 mmol 104 mg, 0.25 mmol 2 1.4 mg, 0.006 mmol 2.0mg, 0.009 mmol 3 6.5 mg, 0.024 mmol 5.9 mg, 0.022 mmol 4 112 117 5 1/42/1 6 88 mg, 0.20 mmol, 76 mg, 0.17 mmol, 83% 72% 7 83 mg, 0.20 mmol 18mg, 0.04 mmol 8 beige white solid light yellow oil products (100 mg,products (20 mg, 0.20 mmol) 0.04 mmol)

Compound 150: To a solution of C₁₈H₂₀BrNO₂ (100 mg, 0.28 mmol) in DMF (2mL), trimethylphenyl-ammonium chloride ((CH₃)₃PhNCl, 102 mg, 0.59 mmol)and t-BuOK (67 mg, 0.60 mmol) were added. The suspension was heated to60° C. under N₂ for 3.5 h, and then (CH₃)₃PhNCl (102 mg, 0.59 mmol) wasadded and heated to 70° C. for 4.5 h. After cooling to room temperature,the reaction mixture was treated with CHCl₃ (10 mL) and 5% NaOH_((aq))(20 mL). The organic layer was washed with brine, dried over MgSO₄,filtered, and evaporated. The crude residue was chromatographed (silicagel, EtOAc/n-hexane=1/4) to afford a yellow solid (83 mg, 0.22 mmol,79%).

Compound 152: To a solution of C₁₈H₁₉BrN₂O₄ (406 mg, 1.00 mmol) in DMF(9 mL), which was cooled to 0° C. and degassed, NaH (40 mg, 1.67 mmol)and CH₃I (0.06 mL, 0.98 mmol) in DMF (1 mL) were added. After stirringfor 10 min, NH₄Cl (111 mg, 2.08 mmol) was added, and then the reactionmixture was treated with diethyl ether (100 mL) and H₂O (100 mL). Theorganic layer was washed with brine, dried over MgSO₄, filtered andevaporated. The crude residue was chromatographed (silica gel,EtOAc/n-hexane=1/2) to afford a yellow solid (123 mg, 0.29 mmol, 30%).

Compound 153: To a solution of C₁₈H₁₉BrClNO₂ (300 mg, 0.75 mmol) in DMF(6 mL), (CH₃)₃PhNCl (542 mg, 3.16 mmol) and t-BuOK (333 mg, 2.97 mmol)were added. The suspension was heated to 60° C. under N₂ for 16 h, andthen heated to 70° C. for 1 h. After cooling to room temperature, thereaction mixture was treated with Et₂O (100 mL) and H₂O (100 mL). Theorganic layer was washed with brine, dried over MgSO₄, filtered, andevaporated. The crude residue was chromatographed (silica gel,EtOAc/n-hexane=1/4) to afford a white solid (189 mg, 0.46 mmol, 61%).

Compound 154: To a solution of C₁₈H₁₉BrFNO₂ (400 mg, 1.05 mmol) in DMF(8 mL), (CH₃)₃PhNCl (727 mg, 4.23 mmol) and t-BuOK (468 mg, 4.17 mmol)were added. The suspension was heated to 70° C. under N₂ for 16 h. Aftercooling to room temperature, the reaction mixture was treated with Et₂O(100 mL) and H₂O (100 mL). The organic layer was washed with brine,dried over MgSO₄, filtered, and evaporated. The crude residue waschromatographed (silica gel, EtOAc/n-hexane=1/4) to afford a white solid(247 mg, 0.63 mmol, 60%).

Compounds 157-159, 165-168 and 171-173: Table 6 is a parameter table.“Parameter 1” is added into the reaction vessel for microwave-assistedheating and dissolved with “parameter 2” mL 2-propanol. “Parameter 3” isadded thereinto, and stirred for 30 minutes. Pd(OAc)₂ “parameter 4”,PPh₃ “parameter 5”, 2 M Na₂CO_(3(aq)) “parameter 6” and “parameter 7” mLH₂O are added and heated to 120° C. for 20 min using microwavesynthesizer. Before the temperature of the solution is decreased,“parameter 8” mL H₂O is added, and then cooled to room temperature,diluted with 10 mL EtOAc, and extracted with 10 mL H₂O. The organiclayer is washed with 5% NaHCO_(3(aq)) followed by brine, added in“parameter 9” mg Darco G-60, stirred for 10 min, filtered by thesintered glass funnel covered with about 1 cm of Celite and a thin layerof Florisil, concentrated, and purified by flash column chromatography(silica gel, “parameter 10”) to obtain “parameter 11”.

TABLE 6 The parameter table for the synthesis of compounds 157-159,165-168 and 171-173 157 158 159 165 166 1 2-fluorophenylboronic2-chlorophenylboronic 2-methoxyphenylboronic 2-fluorophenylboronic2-chlorophenylboronic acid (58 mg, acid (55 mg, acid acid (55 mg, acid(60 mg, 0.41 mmol) 0.35 mmol) (55 mg, 0.36 mmol) 0.39 mmol) 0.38 mmol) 22 1.8 1.8 2 2 3 C₁₉H₂₄BrNO₂ C₁₉H₂₄BrNO₂ C₁₉H₂₄BrNO₂ C₁₉H₂₁BrFNO2C₁₉H₂₁BrFNO₂ (102 mg, 0.27 mmol) (90 mg, 0.24 mmol) (89 mg, 0.24 mmol)(105 mg, 0.27 mmol) (101 mg, 0.26 mmol) 4 1.5 mg, 0.007 mmol 1.6 mg,0.007 mmol 1.7 mg, 0.0076 mmol 1.6 mg, 0.007 mmol 1.4 mg, 0.006 mmol 54.2 mg, 0.016 mmol 8.0 mg, 0.03 mmol 4.7 mg, 0.018 mmol 6.0 mg, 0.023mmol 5.6 mg, 0.021 mmol 6 0.20 mL, 0.40 mmol 0.18 mL, 0.36 mmol 0.18 mL,0.36 mmol 0.19 mL, 0.38 mmol 0.19 mL, 0.38 mmol 7 0.2 0.18 0.18 0.2 0.28 0.7 0.63 0.63 0.7 0.7 9 117 113 99 101 117 10 1/3 1/3 1/2 1/4 1/4 11beige yellow oil light yellow oil light yellow oil yellow oil lightyellow oil products (103 mg, products (58 mg, products (69 mg, products(108 mg, products (50 mg, 0.26 mmol, 0.14 mmol, 0.17 mmol, 0.26 mmol,0.12 mmol, 97%) 59%) 71%) 99%) 47%) 12 C₂₅H₂₆FNO₂ C₂₅H₂₆ClNO₂ C₂₆H₂₉NO₃(69 mg, C₂₅H₂₅F₂NO₂ C₂₅H₂₅ClFNO₂ (103 mg, 0.26 mmol) (31 mg, 0.08 mmol)0.17 mmol) (108 mg, 0.26 mmol) (50 mg, 0.12 mmol) 13 white solid lightyellow light yellow light yellow beige white products (113 mg, solidproducts solid products solid products solid muriate 0.26 mmol) (36 mg,0.08 mmol) (66 mg, 0.15 mmol) (116 mg, 0.26 mmol) products (55 mg, 0.12mmol) 167 168 171 172 173 1 2-fluorophenylboronic 2-chlorophenylboronic2-fluorophenylboronic 2-chlorophenylboronic 2-methoxyphenylboronic acid(45 mg, acid (48 mg, acid (50 mg, acid (56 mg, acid 0.32 mmol) 0.31mmol) 0.36 mmol) 0.36 mmol) (56 mg, 0.37 mmol) 2 1.8 1.7 2 2 2 3C₁₉H₂₁BrClNO₂ C₁₉H₂₁BrClNO₂ C₁₉H₂₂BrN₂O₄ C₁₉H₂₂BrN₂O₄ C₁₉H₂₂BrN₂O₄ (90mg, 0.22 mmol) (84 mg, 0.20 mmol) (98 mg, 0.23 mmol (100 mg, 0.24 mmol)(101 mg, 0.24 mmol) 4 2.0 mg, 0.009 mmol 1.0 mg, 0.004 mmol) 1.7 mg,0.0076 mmol 1.8 mg, 0.0072 mmol 1.8 mg, 0.008 mmol 5 4.7 mg, 0.02 mmol4.4 mg, 0.02 mmol 5.7 mg, 0.022 mmol 6.0 mg, 0.023 mmol 6.5 mg, 0.025mmol 6 0.19 mL, 0.38 mmol 0.16 mL, 0.32 mmol 0.18 mL, 0.36 mmol 0.18 mL,0.36 mmol 0.18 mL, 0.36 mmol 7 0.2 0.17 0.2 0.2 0.2 8 0.7 0.6 0.7 0.70.7 9 105 90 112 101 115 10 1/3 1/3 1/1 1/2 1/1 11 yellow oil beigeyellow beige solid beige white beige yellow products (91 mg, solidproducts products (75 mg, solid products solid products 0.21 mmol, (66mg, 0.15 mmol, mg, 0.17 mmol, (72 mg, 0.16 mmol, (88 mg, 0.20 mmol, 97%)73%) 71%) 66%) 81%) 12 C₂₅H₂₅ClFNO₂ C₂₅H₂₅Cl₂NO₂ C₂₅H₂₅FN₂O₄C₂₅H₂₅ClN₂O₄ C₂₆H₂₈N₂O₅ (72 mg, (91 mg, 0.21 mmol) (66 mg, 0.15 mmol)(56 mg, 0.13 mmol) (72 mg, 0.16 mmol) 0.16 mmol) 13 light yellow beigesolid beige white beige yellow beige white solid products products (72mg, solid products solid products solid products (94 mg, 0.20 mmol) 0.15mmol) (61 mg, 0.13 mmol) (81 mg, 0.17 mmol) (80 mg, 0.16 mmol)

TABLE 7 The analytical data of the compounds in this invention Compoundnumber 7 Name 6-Methoxy-2-propyl-1,2,3,4-tetrahydroisoquinolin- 7-ol ¹HNMR δ 0.84 (t, J = 7.3 Hz, 3H), 1.47-1.59 (m, 2H), (200 MHz, CDCl₃)2.33-2.41 (m, 2H), 2.64 (d, J = 4.8 Hz, 2H), 2.71 (d, J = 4.8 Hz, 2H),3.70 (s, 3H), 3.89 (s, 2H), 6.04 (s, 1H), 6.41 (s, 1H), 6.43 (s, 1H) ¹³CNMR δ 12.5, 20.4, 28.7, 51.5, 55.7, 56.2, 60.8, 111.2, 113.2, (50 MHz,CDCl₃) 125.4, 127.1, 144.5, 146.2 ESI-MS m/z 222 ([M + H]⁺) EIHR-MScalcd for C₁₃H₁₉NO₂ [M]+, 221.1416; found, 221.1442 Compound number 8Name 8-(2,4-Dimethoxyphenyl)-6-methoxy-2-propyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 0.85 (t, J = 7.3 Hz, 3H), 1.38-1.53(m, 2H), (200 MHz, CDCl₃) 2.26-2.37 (m, 3H), 2.63-2.72 (m, 2H),2.85-2.91 (m, 2H), 3.17 (s, 2H), 3.72 (s, 3H), 3.85 (s, 3H), 3.86 (s,3H), 6.55-6.61 (m, 3H), 7.00-7.05 (m, 1H) ¹³C NMR δ 12.4, 20.6, 29.6,50.9, 54.6, 55.8, 56.0, 56.3, 60.7, (50 MHz, CDCl₃) 99.4, 105.1, 110.5,116.8, 122.9, 125.5, 127.1, 132.2, 141.7, 145.5, 158.5, 161.0 EIHR-MScalcd for C₂₁H₂₇NO₄ [M]⁺, 357.1940; found, 357.1915. Compound number 10Name 7-(Benzyloxy)-6-methoxy-1-methyl-3,4-dihydroisoquinoline ¹H NMR δ2.25 (s, 3H), 2.62 (t, J = 7.6 Hz, 2H), 3.57-3.61 (m, (200 MHz, CDCl₃)2H), 3.91 (s, 3H), 5.15 (s, 2H), 6.69 (s, 1H), 7.01 (s, 1H), 7.34-7.48(m, 5H) ¹³C NMR δ 23.8, 26.3, 47.4, 56.5, 72.2, 111.1, 113.0, 122.8, (50MHz, CDCl₃) 128.0, 128.5, 129.1, 132.3, 137.5, 146.9, 152.2, 164.3.Compound number 11 Name7-(Benzyloxy)-6-methoxy-1,2-dimethyl-1,2,3,4-tetrahydroisoquinoline ¹HNMR δ 1.32 (d, J = 6.7 Hz, 3H), 2.48 (s, 3H), 2.65-2.74 (m, (200 MHz,CDCl₃) 1H), 2.78-2.84 (m, 2H), 3.00-3.11 (m, 1H), 3.56 (q, J = 6.5 Hz,1H), 3.84 (s, 3H), 5.10 (s, 2H), 6.59 (s, 1H), 6.60 (s, 1H), 7.23-7.45(m, 5H) ¹³C NMR δ 20.0, 27.5, 43.0, 49.1, 56.4, 59.1, 71.8, 112.1,113.5, (50 MHz, CDCl₃) 126.6, 127.8, 128.2, 128.9, 131.1, 137.7, 146.8,148.7. Compound number 12 Name7-(Benzyloxy)-6-methoxy-1-methyl-2-propyl-1,2,3,4-tetrahydroisoquinoline¹H NMR δ 0.97 (t, J = 7.4 Hz, 3H), 1.68 (d, J = 6.8 Hz, 3H), (200 MHz,CDCl₃) 1.96-2.02 (m, 2H), 2.92-2.99 (m, 2H), 3.01-3.03 (m, 1H),3.08-3.13 (m, 1H), 3.35-3.41 (m, 1H), 3.46-3.53 (m, 1H), 3.86 (s, 3H),4.41 (d, J = 6.8 Hz, 1H), 5.08-5.15 (m, 2H), 6.62 (s, 1H), 6.66 (s, 1H),7.29-7.45 (m, 5H) ¹³C NMR δ 11.2, 18.2, 20.1, 22.9, 43.5, 53.7, 55.9,57.3, 71.2, (100 MHz, CDCl₃) 111.5, 112.5, 122.4, 124.7, 127.3, 127.8,128.4, 136.4, 147.3, 149.5 EIHR-MS calcd for C₂₁H₂₇NO₂ [M]+, 325.2042;found, 325.2022. Compound number 13 Name6-Methoxy-1,2-dimethyl-1,2,3,4-tetrahydroisoquinolin- 7-ol ¹H NMR δ 1.59(d, J = 6.7 Hz, 3H), 2.87 (s, 3H), 3.00-3.07 (m, (200 MHz, CD₃OD) 2H),3.34-3.38 (m, 1H), 3.49-3.63 (m, 1H), 3.84 (s, 3H), 4.34 (q, J = 6.7 Hz,1H), 6.63 (s, 1H), 6.75 (s, 1H) ¹³C NMR δ 19.0, 24.5, 39.9, 47.8, 56.4,60.1, 112.4, 114.2, 122.1, (50 MHz, CD₃OD) 126.5, 147.0, 149.1. Compoundnumber 14 Name6-Methoxy-1-methyl-2-propyl-1,2,3,4-tetrahydroisoquinolin- 7-ol ¹H NMR δ0.88 (t, J = 7.3 Hz, 3H), 1.66 (d, J = 6.7 Hz, 3H), (400 MHz, CDCl₃)1.86-1.98 (m, 2H), 2.94-3.03 (m, 2H), 3.04-3.09 (m, 2H), 3.39-3.41 (m,1H), 3.45-3.50 (m, 1H), 3.76 (s, 3H), 4.41 (q, J = 6.6 Hz, 1H), 6.56 (s,1H), 6.60 (s, 1H) ¹³C NMR δ 11.1, 17.7, 20.0, 22.5, 43.6, 53.4, 56.0,57.5, 110.7, (100 MHz, CDCl₃) 112.4, 120.4, 124.2, 145.1, 146.8 EIHR-MScalcd for C₁₄H₂₁NO₂ [M]⁺, 235.1572; found, 235.1601. Compound number 15Name 8-(2,4-Dimethoxyphenyl)-6-methoxy-1,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 1.02 (d, J = 8.0 Hz, 3H), 2.56(s, 3H), 2.77 (dd, J = 16.0, (400 MHz, CDCl₃) 4.0 Hz, 1H), 2.93-2.98 (m,1H), 3.06-3.16 (m, 1H), 3.22-3.31 (m, 1H), 3.77 (s, 3H), 3.86 (s, 3H),3.88 (s, 3H), 6.58-6.61 (m, 2H), 6.63 (s, 1H), 6.98 (dd, J = 6.1, 2.8Hz, 1H) ¹³C NMR δ 16.1, 25.3, 41.4, 44.1, 55.5, 55.7, 55.9, 99.3, 105.1,(100 MHz, CDCl₃) 110.4, 116.1, 122.7, 123.2, 128.7, 131.5, 142.3, 145.5,158.5, 160.0 EIHR-MS calcd for C₂₀H₂₅NO₄ [M]⁺, 343.1784; found,343.1791. Compound number 16 Name8-(2,4-Dimethoxyphenyl)-6-methoxy-1-methyl-2-propyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 0.87 (t, J = 8.0 Hz, 3H),0.98 (d, J = 4.0 Hz, 3H), (400 MHz, CDCl₃) 1.49 (q, J = 8.0 Hz, 2H),2.44-2.54 (m, 3H), 2.85-2.88 (m, 1H), 2.90-3.05 (m, 1H), 3.19-3.30 (m,1H), 3.55 (q, J = 8.0 Hz, 1H), 3.72 (s, 3H), 3.86 (s, 3H), 3.87 (s, 3H),5.30 (s, 1H), 6.57-6.62 (m, 3H), 7.10 (d, J = 8.0 Hz, 1H) ¹³C NMR δ12.1, 19.3, 21.3, 24.7, 42.8, 53.1, 55.46, 55.49, 55.6, (100 MHz, CDCl₃)55.9, 99.2, 104.7, 110.6, 116.4, 122.9, 124.3, 132.6, 133.3, 141.4,145.1, 157.5, 160.8 ESI-MS m/z 371.0 [M]⁺ Compound number 21 Name6-Methoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-7- ol ¹H NMR δ2.71-2.96 (m, 8H), 3.61 (s, 2H), 3.84 (s, 3H), 6.57 (s, (200 MHz, CDCl₃)2H), 7.16-7.34 (m, 5H) ¹³C NMR δ 28.8, 34.1, 51.2, 55.6, 56.0, 60.4,110.8, 112.4, 125.5, (50 MHz, CDCl₃) 126.2, 127.3, 128.5, 128.9, 140.5,143.8, 145.4 Compound number 29 Name6-Methoxy-8-(2-methoxyphenyl)-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.57-2.66 (m, 2H), 2.72-2.81 (m, 4H), 2.85-2.92 (m, (200MHz, CDCl₃) 2H), 3.25 (s, 2H), 3.74 (s, 3H), 3.86 (s, 3H), 6.63 (s, 1H),6.97-7.06 (m, 2H), 7.11-7.28 (m, 6H), 7.32-7.40 (m, 1H) ¹³C NMR δ 29.2,34.0, 50.5, 54.2, 55.7, 56.0, 60.0, 110.2, 111.3, (50 MHz, CDCl₃) 120.9,122.8, 124.1, 125.2, 126.0, 126.2, 128.4, 128.7, 129.3, 131.6, 140.5,141.1, 145.2, 157.1 ESI-MS m/z 390 ([M + H]⁺) EIHR-MS calcd forC₂₅H₂₈NO₃ [M + H]⁺, 390.2069; found, 390.2054 Compound number 30 Name6-Methoxy-8-(4-methoxyphenyl)-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.59-2.68 (m, 2H), 2.73-2.82 (m, 4H), 2.92, (t, J = 5.8Hz, (200 MHz, CDCl₃) 2H), 3.29 (s, 2H), 3.83 (s, 3H), 3.87 (s, 3H), 6.62(s, 1H), 6.93-6.94, (m, 1H), 6.98-6.99 (m, 1H), 7.12-7.24 (m, 7H) ¹³CNMR δ 29.4, 34.0, 50.6, 55.0, 55.3, 56.1, 60.2, 110.0, 114.1, (50 MHz,CDCl₃) 125.4, 125.9, 126.0, 127.6, 128.4, 128.7, 130.9, 140.4, 141.2,145.4, 158.9 ESI-MS m/z 390 ([M + H]⁺), 412 ([M + Na]⁺) EIHR-MS calcdfor C₂₅H₂₈NO₃ [M + H]⁺, 390.2069; found, 390.2067 Compound number 31Name6-Methoxy-8-(3-methoxyphenyl)-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.59-2.68 (m, 2H), 2.74-2.80 (m, 4H), 2.89-2.95 (m, (200MHz, CDCl₃) 2H), 3.31 (s, 2H), 3.78 (s, 3H), 3.86 (s, 3H), 6.63 (s, 1H),6.78-6.83, (m, 2H), 6.86-6.94 (m, 1H), 7.11-7.24 (m, 5H), 7.30-7.40 (m.1H) ¹³C NMR δ 29.2, 33.8, 50.4, 54.7, 55.2, 56.0, 60.0, 110.1, 113.3,(50 MHz, CDCl₃) 115.2, 122.1, 125.3, 125.4, 126.1, 126.2, 128.4, 128.7,129.6, 136.9, 140.3, 141.0, 145.4, 159.7 ESI-MS m/z 390.2 ([M + H]⁺),412.2 ([M + Na]⁺) EIHR-MS calcd for C₂₅H₂₈NO₃ [M + H]⁺, 390.2069; found,390.2064 Compound number 32 Name6-Methoxy-8-(3,4,5-trimethoxyphenyl)-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.62-2.71 (m, 2H), 2.78-2.85 (m,4H), 2.91-2.96 (m, (200 MHz, CDCl₃) 2H), 3.32 (s, 2H), 3.90 (s, 6H),3.91 (s, 3H), 3.92 (s, 3H), 5.41 (s, 1H), 6.46 (s, 2H), 6.65 (s, 1H),7.13-7.30 (m, 5H) ¹³C NMR δ 29.5, 34.1, 50.5, 54.5, 56.2, 60.3, 61.0,106.6, 110.3, (50 MHz, CDCl₃) 125.7, 126.2, 126.3, 128.5, 128.8, 131.0,137.1, 140.3, 140.9, 145.4, 153.5 ESI-MS m/z 449 ([M]⁺) EIHR-MS calcdfor C₂₇H₃₂NO₅ [M + H]⁺, 450.2280; found, 450.2268 Compound number 33Name 6-Methoxy-2-phenethyl-8-phenyl-1,2,3,4-tetrahydroisoquinolin- 7-ol¹H NMR δ 2.57-2.66 (m, 2H), 2.72-2.79 (m, 4H), 2.89-2.94 (m, (200 MHz,CDCl₃) 2H, 3.28 (s, 2H), 3.85 (s, 3H), 6.63 (s, 1H), 7.10-7.14 (m, 2H),7.19-7.25 (m, 5H), 7.32-7.48 (m, 3H) ¹³C NMR δ 29.3, 33.9, 50.5, 54.9,56.1, 60.1, 110.1, 125.4, 126.1, (50 MHz, CDCl₃) 126.4, 127.5, 128.4,128.6, 128.7, 129.8, 135.7, 140.3, 141.0, 145.4 ESI-MS m/z 360 ([M +H]⁺) EIHR-MS calcd for C₂₄H₂₆NO₂ [M + H]⁺, 360.1964; found, 360.1956Compound number 34 Name6-Methoxy-8-(2-methylthiophenyl)-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.37 (s, 3H), 2.57-2.66 (m, 2H),2.72-2.81 (m, 4H), (200 MHz, CDCl₃) 2.89-2.92 (m, 2H), 3.22 (s, 2H),3.88 (s, 3H), 6.67 (s, 1H), 7.12-7.22 (m, 8H), 7.25-7.29 (m, 1H) ¹³C NMRδ 15.2, 29.2, 34.0, 50.5, 53.8, 56.0, 60.0, 110.6, 124.1, (50 MHz,CDCl₃) 124.7, 125.0, 125.6, 125.9, 126.1, 128.4, 128.6, 128.8, 130.1,133.9, 138.6, 140.5, 141.0, 145.2 ESI-MS m/z 406 ([M + H]⁺) EIHR-MScalcd for C₂₅H₂₈NO₂S [M + H]⁺, 406.1841; found, 406.1836 Compound number35 Name 6-Methoxy-8-(4-methylthiophenyl)-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.51 (s, 3H), 2.63-2.68 (m, 2H),2.74-2.81 (m, 4H), (200 MHz, CDCl₃) 2.89-2.95 (m, 2H), 3.29 (s, 2H),3.88 (s, 3H), 6.63 (s, 1H), 7.14-7.21 (m, 6H), 7.25-7.33 (m, 3H) ¹³C NMRδ 15.7, 29.4, 33.9, 50.5, 55.0, 56.1, 60.2, 110.1, 125.5, (50 MHz,CDCl₃) 125.6, 126.1, 126.5, 128.4, 128.8, 130.3, 137.6, 140.4, 141.1,145.4 ESI-MS 406 ([M + H]⁺) EIHR-MS calcd for C₂₅H₂₈NO₂S [M + H]⁺,406.1841; found, 406.1839 Compound number 36 Name8-(Benzo[1,3]dioxol-5-yl)-6-methoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.61-2.70 (m, 2H), 2.73-2.84 (m,4H), 2.89-2.94 (m, (200 MHz, CDCl₃) 2H), 3.30 (s, 2H), 3.88 (s, 3H),5.43 (bs, 1H), 6.00 (bs, 2H), 6.63 (s, 1H), 6.68-6.73 (m, 2H), 6.86-6.90(m, 1H), 7.16-7.26 (m, 5H) ¹³C NMR δ 29.5, 34.1, 50.6, 55.0, 56.2, 60.3,101.2, 108.7, 110.1, (50 MHz, CDCl₃) 110.4, 123.1, 125.5, 125.9, 126.1,128.5, 128.8, 129.0, 140.4, 141.2, 145.3, 147.0, 147.8 ESI-MS m/z 404([M + H]⁺) EIHR-MS calcd for C₂₅H₂₆NO₄ [M + H]⁺, 404.1862; found,404.1849 Compound number 37 Name8-(2-Cyanophenyl)-6methoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.61-2.80 (m, 6H), 2.87-2.94 (m, 2H), 3.12 (d, J = 14.8Hz, (200 MHz, CDCl₃) 1H), 3.32 (d, J = 14.9 Hz, 1H), 3.90 (s, 3H), 6.68(s, 1H), 7.12-7.29 (m, 5H), 7.35 (ddd, J = 7.7, 1.3, 0.6 Hz, 1H), 7.46(td, J = 7.6, 1.3 Hz, 1H), 7.65 (td, J = 7.6, 1.5 Hz, 1H), 7.77 (ddd, J= 7.7, 1.4, 0.5 Hz, 1H) ¹³C NMR δ 29.2, 34.0, 50.3, 54.3, 56.1, 60.0,111.2, 114.0, 118.2, (50 MHz, CDCl₃) 122.2, 125.1, 126.0, 126.2, 128.1,128.5, 128.8, 131.0, 132.8, 133.2, 140.3, 141.3, 145.3 ESI-MS m/z 385([M + H]⁺) EIHR-MS calcd for C₂₅H₂₅N₂O₂ [M + H]⁺, 385.1916; found,385.1910 Compound number 38 Name6-Methoxy-8-(2-nitrophenyl)-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.63-2.82 (m, 6H), 2.87-2.91 (m. 2H), 3.14 (d, J = 15.0Hz, (200 MHz, CDCl₃) 1H), 3.40 (d, J = 14.9 Hz, 1H), 3.87 (s, 3H), 6.65(s, 1H), 7.12-7.26 (m, 5H), 7.30-7.36 (m, 1H), 7.48-7.58 (m, 1H),7.60-7.70 (m, 1H), 8.01-8.08 (m, 1H) ¹³C NMR δ 28.9, 33.9, 50.3, 54.0,56.1, 59.7, 110.6, 121.9, 124.6, (50 MHz, CDCl₃) 124.8, 125.8, 126.2,128.5, 128.8, 131.0, 132.6, 133.1, 140.3, 140.7, 145.0, 149.6 ESI-MS m/z405 ([M + H]⁺) EIHR-MS calcd for C₂₄H₂₅N₂O₄ [M + H]⁺, 405.1814; found,405.1800 Compound number 39 Name8-(2-Chlorophenyl)-6-methoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.59-2.69 (m, 2H), 2.72-2.82 (m, 4H), 2.88-2.91 (m, (200MHz, CDCl₃) 2H), 3.21 (d, J = 3.7 Hz, 2H), 3.85 (s, 3H), 6.65 (s, 1H),7.11-7.22 (m, 6H), 7.28-7.33 (m 2H), 7.43-7.52 (m, 1H) ¹³C NMR δ 29.1,33.9, 50.4, 53.9, 56.0, 59.9, 110.5, 123.6, 125.4, (50 MHz, CDCl₃)125.6, 126.0, 127.0, 128.4, 128.7, 129.1, 129.7, 131.5, 134.1, 134.9,140.4, 141.1, 145.2 ESI-MS m/z 394 ([M + H]⁺) EIHR-MS calcd forC₂₄H₂₅ClNO₂ [M + H]⁺, 394.1574; found, 394.1571 Compound number 40 Name8-(2-Acetylphenyl)-6methoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.15 (s, 3H), 2.53-3.00 (m. 8H), 3.05 (d, J = 15.4 Hz,(200 MHz, CDCl₃) 1H), 3.28 (d, J = 15.1 Hz, 1H), 3.87 (s, 3H), 5.59 (bs,1H), 6.65 (s, 1H), 7.06-7.61 (m, 8H), 7.76 (dd, J = 7.5, 1.6 Hz, 1H)ESI-MS m/z 402 ([M + H]⁺) EIHR-MS calcd for C₂₆H₂₈NO₃ [M + H]⁺,402.2069; found, 402.2061 Compound number 41 Name8-(2-Fluorophenyl)-6-methoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.61-2.68 (m, 2H), 2.72-2.84 (m, 4H), 2.88-2.92 (m, (200MHz, CDCl₃) 2H), 3.23 (d, J = 15.0 Hz, 1H), 3.37 (d, J = 15.0 Hz, 1H),3.89 (s, 3H), 5.52 (s, 1H), 6.67 (s, 1H), 7.12-7.35 (m, 9H) ¹³C NMR δ29.3, 34.0, 50.5, 54.3, 56.1, 60.1, 110.7, 115.9 (d, J = 22.3 Hz), (50MHz, CDCl₃) 119.7, 123.1 (d, J = 17.7 Hz), 124.2, 125.6, 126.1, 128.4,128.8, 129.7 (d, J = 7.9 Hz), 132.0, 140.1, 141.5, 145.2, 160.1 (d, J =244 Hz) ESI-MS m/z 378.2 ([M + H]⁺) Compound number 42 Name(2-Methylphenyl)-6-methoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.09 (s, 3H), 2.57-2.65 (m, 2H), 2.71-2.81 (m, 4H), (200MHz, CDCl₃) 2.90-2.92 (m, 2H), 3.02 (d, J = 15.3 Hz, 1H), 3.25 (d, J =15.2 Hz, 1H), 3.89 (s, 3H), 5.33 (s, 1H), 6.64 (s, 1H), 7.09-7.31 (m,9H) ¹³C NMR δ 19.7, 29.4, 33.9, 50.6, 54.6, 56.1, 60.2, 110.0, 125.5,(50 MHz, CDCl₃) 125.6, 126.1, 128.0, 128.4, 128.8, 129.8, 130.3, 135.0,137.0, 140.4, 140.7, 145.3 ESI-MS m/z 374.2 ([M + H]⁺) Compound number43 Name8-(2-Isopropylphenyl)-6-methoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 1.12-1.17 (m, 3H), 1.26-1.30 (m, 3H), 2.65-2.94 (m, (200MHz, CDCl₃) 8H), 3.12-3.20 (m, 2H), 3.63-3.65 (m, 1H), 3.91 (s, 3H),5.30 (s, 1H), 6.67 (s, 1H), 7.06-7.42 (m, 9H) ¹³C NMR δ 24.0, 24.5,29.3, 30.3, 33.9, 50.7, 54.7, 56.0, 60.2, (50 MHz, CDCl₃) 110.0, 125.5,125.8, 126.1, 128.4, 128.7, 128.9, 129.9, 133.5, 140.3, 141.0, 145.2,147.7 ESI-MS m/z 402.2 ([M + H]⁺) Compound number 44 Name8-(3,5-Dimethoxyphenyl)-6-methoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.58-2.72 (m, 2H), 2.73-2.82 (m,4H), 2.93 (t, J = 3.0 Hz, (200 MHz, CDCl₃) 2H), 3.33 (s, 2H), 3.79 (s,6H), 3.90 (s, 3H), 5.36 (s, 1H), 6.40 (s, 1H), 6.41 (s, 1H), 6.64 (s,1H) 6.46-6.50 (m, 1H), 7.11-7.23 (m, 4H), 7.27-7.32 (m, 1H) ¹³C NMR δ29.5, 34.1, 50.6, 54.8, 55.5, 56.2, 60.2, 100.0, 107.6, (50 MHz, CDCl₃)110.3, 125.6, 126.1, 126.3, 128.5, 128.8, 137.5, 140.4, 140.8, 145.4,161.0 ESI-MS m/z 420 ([M + H]⁺) EIHR-MS calcd for C₂₆H₃₀NO₄ [M + H]⁺,420.2175; found, 420.2167 Compound number 45 Name8-(2,3-Dimethoxyphenyl)-6-methoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.54-2.86 (m, 6H), 2.87-3.00 (m,2H), 3.28 (s, 2H), (200 MHz, CDCl₃) 3.62 (s, 3H), 3.89 (s, 3H), 3.90 (s,3H), 5.46 (s, 1H), 6.65 (s, 1H), 6.73 (dd, J = 7.6, 1.5 Hz, 1H), 6.95(dd, J = 8.2, 1.4 Hz, 1H), 7.07-7.29 (m, 6H) ¹³C NMR δ 29.3, 33.9, 50.6,54.2, 55.8, 56.0, 60.0, 60.8, 110.2, (50 MHz, CDCl₃) 112.0, 122.6,123.1, 124.3, 125.3, 126.0, 126.2, 128.4, 128.8, 129.7, 140.5, 140.9,145.1, 147.0, 153.1 ESI-MS m/z 420 ([M + H]⁺) EIHR-MS calcd forC₂₆H₃₀NO₄ [M + H]⁺, 420.2175; found, 420.2159 Compound number 60 Name8-Bromo-6-methoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinolin- 7-ol ¹H NMRδ 2.70-3.01 (m, 8H), 3.64 (s, 2H), 3.86 (s, 3H), 6.58 (s, (200 MHz,CDCl₃) 1H), 7.17-7.37 (m, 5H) ¹³C NMR δ 29.3, 34.0, 50.4, 56.2, 56.4,60.2, 109.0, 110.1, 126.2, (50 MHz, CDCl₃) 126.5, 127.3, 128.6, 128.9,140.3, 141.2, 145.6 ESI-MS calcd for C₁₈H₂₁BrNO₂ m/z 362.1 EIHR-MS calcdfor C₁₈H₂₁BrNO₂ [M + H]⁺, 362.0755; found, 362.0782 Compound number 61Name 6-Methoxy-2-(2-(1-naphthyl)ethyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.68-2.97 (m, 6H), 3.23-3.47 (m, 2H), 3.68 (s, 2H), (200MHz, CDCl₃) 3.83 (s, 3H), 6.58 (s, 1H), 6.60 (s, 1H), 7.28-7.58 (m, 4H),7.64-7.91 (m, 2H), 8.00-8.17 (m, 1H) ¹³C NMR δ 28.8, 31.1, 51.3, 55.6,56.0, 59.4, 110.8, 112.6, 123.9, (50 MHz, CDCl₃) 125.4, 125.6, 125.7,126.1, 126.7, 127.0, 127.1, 128.9, 132.0, 134.0, 136.5, 144.0, 145.6EIHR-MS calcd for C₂₂H₂₃NO₂ [M]⁺, 333.1729; found, 333.1721 Compoundnumber 62 Name2-(2-(3-indolyl)ethyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin- 7-ol ¹HNMR δ 2.76-2.94 (m, 6H), 3.00-3.15 (m, 2H), 3.66 (s, 2H), (200 MHz,CDCl₃) 3.85 (s, 3H), 6.59 (s, 1H), 6.61 (s, 1H), 7.02-7.24 (m, 3H),7.32-7.40 (m, 1H), 7.61-7.69 (m, 1H), 8.03 (s, 1H) ¹³C NMR δ 23.2, 28.7,51.1, 55.5, 55.9, 58.9, 110.7, 111.1, 112.3, (50 MHz, CDCl₃) 114.4,118.8, 119.2, 121.5, 121.9, 125.5, 127.3, 127.5, 136.2, 143.7, 145.3EIHR-MS calcd for C₂₀H₂₂N₂O₂ [M]⁺, 322.1681; found, 322.1675 Compoundnumber 63 Name6-Methoxy-2-(2-nitrophenethyl)-1,2,3,4-tetrahydroisoquinolin- 7-ol ¹HNMR δ 2.78-2.86 (m, 6H), 3.16-3.23 (m, 2H), 3.63 (s, 2H), (200 MHz,CDCl₃) 3.85 (s, 3H), 6.58 (m, 1H), 6.59 (s, 1H), 7.36-7.44 (m, 2H),7.49-7.53 (m, 1H), 7.92 (dd, J = 8.1, 1.3 Hz, 1H) ¹³C NMR δ 28.9, 31.0,50.9, 55.5, 56.1, 58.8, 110.8, 112.4, 125.6, (50 MHz, CDCl₃) 127.4,132.7, 133.2, 135.5, 143.8, 145.4, 149.6 ESI-MS m/z 329.2 ([M + H]⁺),351.1 ([M + Na]⁺) Compound number 64 Name6-Methoxy-2-(3-nitrophenethyl)-1,2,3,4-tetrahydroisoquinolin- 7-ol ¹HNMR δ 2.73-2.89 (m, 6H), 2.95-3.03 (m, 2H), 3.58 (s, 2H), (200 MHz,CDCl₃) 3.82 (s, 1H), 5.73 (s, 1H), 6.55 (s, 2H), 7.42 (t, J = 7.8 Hz,1H), 7.52, (d, J = 7.6 Hz, 1H), 8.03-809 (m, 2H) ¹³C NMR δ 28.8, 33.6,51.2, 55.6, 56.1, 59.4, 110.8, 112.4, 121.4, (50 MHz, CDCl₃) 123.7,125.5, 127.0, 129.4, 135.3, 142.5, 143.9, 145.5, 148.4 ESI-MS m/z 329.2([M + H]⁺), 351.1 ([M + Na]⁺) Compound number 65 Name6-Methoxy-2-(4-nitrophenethyl)-1,2,3,4-tetrahydroisoquinolin- 7-ol ¹HNMR δ 2.74-2.86 (m, 6H), 2.97-3.04 (m, 2H), 3.60 (s, 2H), (200 MHz,CDCl₃) 3.85 (s, 3H), 6.57 (s, 2H), 7.36-7.43 (m, 2H), 8.11-8.18 (m, 2H)¹³C NMR δ 28.8, 33.9, 51.2, 55.6, 56.1, 59.3, 110.8, 112.4, 123.8, (50MHz, CDCl₃) 125.5, 127.0, 129.7, 143.9, 145.5, 146.6, 148.5 ESI-MS ESIMSm/z 329.1 ([M + H]⁺) Compound number 66 Name2-(4-Chlorophenethyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin- 7-ol ¹HNMR δ 2.66-2.93 (m, 8H), 3.58 (s, 2H), 3.83 (s, 3H), 6.54 (s, (200 MHz,CDCl₃) 1H), 6.56 (s, 1H), 7.11-7.19 (m, 2H), 7.21-7.28 (m, 2H) ¹³C NMR δ28.7, 33.3, 51.2, 55.5, 56.0, 60.0, 110.8, 112.5, 125.4, (50 MHz, CDCl₃)127.0, 128.6, 130.2, 131.9, 138.9, 143.9, 145.5 EIHR-MS calcd forC₁₈H₂₀ClNO₂ [M]⁺, 317.1183; found, 317.1180 Compound number 67 Name2-(2,4-Dichlorophenethyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin- 7-ol¹H NMR δ 2.63-2.91 (m, 8H), 3.61 (s, 2H), 3.83 (s, 3H), 6.56 (s, (200MHz, CDCl₃) 2H), 7.15-7.24 (m, 2H), 7.33-7.43 (m, 1H) ¹³C NMR δ 28.8,31.0, 51.0, 55.5, 56.0, 57.8, 110.8, 112.5, 125.5, (50 MHz, CDCl₃)127.1, 127.2, 129.3, 131.7, 132.6, 134.8, 136.6, 143.9, 145.4 EIHR-MScalcd for C₁₈H₁₉Cl₂NO₂ [M]⁺, 351.0793; found, 351.0799 Compound number68 Name 2-(4-Bromophenethyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.67-2.92 (m, 8H), 3.59 (s, 2H), 3.84 (s, 3H), 6.57 (s,(200 MHz, CDCl₃) 2H), 7.07-7.15 (m, 2H), 7.37-7.44 (m, 2H) ¹³C NMR δ28.8, 33.5, 51.2, 55.6, 56.1, 60.0, 110.8, 112.4, 120.0, (50 MHz, CDCl₃)125.5, 127.2, 130.6, 130.6, 139.5, 143.9, 145.4 EIHR-MS calcd forC₁₈H₂₀BrNO₂ [M]⁺, 313.0677; found, 313.0676 Compound number 69 Name2-(3-Bromophenethyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin- 7-ol ¹HNMR δ 2.67-2.93 (m, 8H), 3.59 (s, 2H), 3.84 (s, 3H), 6.57 (s, (200 MHz,CDCl₃) 2H), 7.13-7.19 (m, 2H), 7.28-7.40 (m, 2H) ¹³C NMR δ 28.8, 33.7,51.2, 55.6, 56.1, 60.0, 110.8, 112.4, 122.5, (50 MHz, CDCl₃) 125.5,127.2, 127.6, 129.3, 130.1, 131.9, 142.9, 143.9, 145.4 EIHR-MS calcd forC₁₈H₂₀BrNO₂ [M]⁺, 313.0677; found, 313.0665 Compound number 70 Name6-Methoxy-2-(3-Methoxyphenethyl)-1,2,3,4-tetrahydroisoquinolin- 7-ol ¹HNMR δ 2.69-2.96 (m, 8H), 3.60 (s, 2H), 3.80 (s, 3H), 3.84 (s, (200 MHz,CDCl₃) 3H), 6.57 (s, 2H), 6.72-6.88 (m, 3H), 7.16-7.28 (m, 1H) ¹³C NMR δ28.8, 34.1, 51.2, 55.3, 55.6, 56.1, 60.3, 110.8, 111.5, (50 MHz, CDCl₃)112.1, 112.4, 114.6, 121.2, 125.5, 127.2, 129.5, 142.1, 143.8, 145.4,159.7 EIHR-MS calcd for C₁₉H₂₃NO₃ [M]⁺, 313.1678; found, 313.1678Compound number 71 Name2-Heptyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 0.85-0.88(m, 3H), 1.18-1.50 (m, 8H), 1.50-1.70 (m, (200 MHz, CDCl₃) 2H),2.43-2.51 (m, 2H), 2.66-2.71 (m, 2H), 2.78-2.81 (m, 2H), 3.50 (s, 2H),3.83 (s, 3H), 6.55 (s, 2H) ¹³C NMR δ 14.2, 22.8, 27.3, 27.8, 28.8, 29.4,32.0, 51.2, 55.7, (50 MHz, CDCl₃) 56.0, 58.7, 110.8, 112.5, 125.6,127.6, 143.8, 145.4 ESI-MS m/z 278.2 ([M + H]⁺) Compound number 72 Name6-Methoxy-2-octyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 0.88 (s,3H), 1.18-1.50 (m, 10H), 1.50-1.70 (m, 2H), (200 MHz, CDCl₃) 2.43-2.51(m, 2H), 2.66-2.71 (m, 2H), 2.78-2.81 (m, 2H), 3.50 (s, 2H), 3.84 (s,3H), 6.56 (s, 2H) ¹³C NMR δ 14.3, 22.8, 27.3, 27.8, 28.8, 29.4, 29.7,32.0, 51.2, (50 MHz, CDCl₃) 55.8, 56.1, 58.7, 110.8, 112.5, 125.6,127.5, 143.8, 145.4 ESI-MS m/z 292.2 ([M + H]⁺) Compound number 73 Name6-Methoxy-2-nonyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 0.88 (s,3H), 1.28 (bs, 12H), 1.50-1.70 (m, 2H), (200 MHz, CDCl₃) 2.43-2.51 (m,2H), 2.69-2.72 (m, 2H), 2.79-2.81 (m, 2H), 3.50 (s, 2H), 3.83 (s, 3H),6.55 (s, 2H) ¹³C NMR δ 14.3, 22.8, 27.3, 27.8, 28.8, 29.4, 29.7, 32.0,51.2, (50 MHz, CDCl₃) 55.7, 56.1, 58.7, 110.8, 112.5, 125.7, 127.5,143.8, 145.4 ESI-MS m/z 306.2 ([M + H]⁺) Compound number 74 Name2-(3,4-Dimethoxyphenethyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin- 7-ol¹H NMR δ 2.68-2.93 (m, 8H), 3.60 (s, 2H), 3.84 (s, 3H), 3.86 (s, (200MHz, CDCl₃) 3H), 3.87 (s, 3H), 6.57 (s, 2H), 6.73-6.84 (m, 3H) ¹³C NMR δ28.8, 33.6, 51.3, 55.6, 56.0, 60.5, 110.8, 111.3, 112.1, (50 MHz, CDCl₃)112.4, 120.6, 125.5, 127.2, 133.0, 143.8, 145.4, 147.4, 148.9 EIHR-MScalcd for C₂₀H₂₅NO₄ [M]⁺, 343.1784; found, 343.1788 Compound number 75Name 2-(2-Chlorophenethyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin- 7-ol¹H NMR δ 2.68-2.90 (m, 6 H), 2.98-3.11 (m, 2H), 3.63 (s, 2H), (200 MHz,CDCl₃) 3.83 (s, 3H), 6.57 (s, 2H), 7.09-7.24 (m, 2H), 7.24-7.39 (m, 2H)¹³C NMR δ 28.8, 31.6, 51.0, 55.5, 56.0, 58.1, 110.8, 112.5, 125.5, (50MHz, CDCl₃) 127.0, 127.2, 127.7, 129.6, 131.0, 134.1, 138.0, 143.8,145.4 ESI-MS m/z 318 ([M + H]⁺), 340 ([M + Na]⁺) EIHR-MS calcd forC₁₈H₂₁ClNO₂ [M + H]⁺, 318.1261; found, 318.1253 Compound number 76 Name2-(2-Fluorophenethyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin- 7-ol ¹HNMR δ 2.68-2.89 (m, 6H), 2.89-3.01 (m, 2H), 3.61 (s, 2H), (200 MHz,CDCl₃) 3.83 (s, 3H), 6.56 (s, 2H), 6.94-7.11 (m, 2H), 7.12-7.30 (m, 2H)¹³C NMR δ 27.2, 28.8, 51.1, 55.5, 56.0, 58.6, 110.8, 112.5, (50 MHz,CDCl₃) 115.4 (J = 22.1 Hz), 124.1 (J = 3.1 Hz), 125.5, 127.2 (J = 15.9Hz), 127.3, 127.9 (J = 7.9 Hz), 131.1 (J = 4.8 Hz), 143.8, 145.4, 161.3(J = 243 Hz) ESI-MS m/z 302 ([M + H]⁺) EIHR-MS calcd for C₁₈H₂₁FNO₂ [M +H]⁺, 302.1556; found, 302.1554 Compound number 77 Name6-Methoxy-2-(3-(4-nitrophenyl)propyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 1.84-2.05 (m, 2H), 2.44-2.56 (m, 2H), 2.63-2.74 (m, (200MHz, CDCl₃) 2H), 2.74-2.88 (m, 4H), 3.50 (s, 2H), 3.83 (s, 3H), 6.54 (s,1H), 6.56 (s, 1H), 7.30-7.42 (m, 2H), 8.09-8.20 (m, 2H) ¹³C NMR δ 28.4,28.8, 33.6, 51.2, 55.6, 56.0, 57.3, 110.8, 112.4, (50 MHz, CDCl₃) 123.7,125.5, 127.2, 129.4, 143.8, 145.4, 146.4, 150.3 EIHR-MS calcd forC₁₉H₂₃N₂O₄ [M + H]⁺, 343.1658; found, 343.1661 Compound number 78 Name6-Methoxy-2-(3-(2-nitrophenyl)propyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 1.80-2.09 (m, 2H), 2.44-2.63 (m, 2H), 2.64-2.75 (m, (200MHz, CDCl₃) 2H), 2.76-2.88 (m, 2H), 2.88-3.07 (m, 2H), 3.51 (s, 2H),3.83 (s, 3H), 6.55 (s, 1H), 6.56 (s, 1H), 7.28-7.43 (m, 2H), 7.45-7.58(m, 1H), 7.83-7.95 (m, 1H) ¹³C NMR δ 28.2, 28.8, 31.0, 51.0, 55.7, 56.0,57.7, 110.8, 112.4, (50 MHz, CDCl₃) 124.8, 125.6, 127.1, 127.4, 132.2,133.0, 137.4, 143.8, 145.4, 149.5 EIHR-MS calcd for C₁₉H₂₃N₂O₄ [M + H]⁺,343.1658; found, 343.1661 Compound number 85 Name8-Bromo-6-methoxy-2-(4-nitrophenethyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.71-2.93 (m, 6H), 2.97-3.10 (m, 2H), 3.62 (s, 2H), (200MHz, CDCl₃) 3.87 (s, 3H), 6.59 (s, 1H), 7.37-7.46 (m, 2H), 8.12-8.20 (m,2H) ¹³C NMR δ 29.3, 33.9, 50.4, 56.1, 56.4, 59.1, 108.8, 110.1, 123.8,(50 MHz, CDCl₃) 126.2, 127.1, 129.7, 141.3, 145.6, 146.6, 148.4 ESI-MSm/z 407 ([M + H]⁺), 429 ([M + Na]⁺) EIHR-MS calcd for C₁₈H₂₀BrN₂O₄ [M +H]⁺, 407.0606; found, 407.0585 Compound number 95 Name8-Bromo-2-(2-chlorophenethyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.72-2.93 (m, 6H), 2.98-3.15 (m, 2H), 3.66 (s, 2H), (200MHz, CDCl₃) 3.86 (s, 3H), 6.11 (bs, 1H), 6.58 (s, 1H), 7.10-7.25 (m,2H), 7.25-7.41 (m, 2H) ¹³C NMR δ 29.4, 31.6, 50.2, 56.2, 56.4, 58.0,108.9, 110.2, 126.6, (50 MHz, CDCl₃) 127.0, 127.3, 127.8, 129.7, 131.0,134.2, 138.0, 141.2, 145.5 ESI-MS m/z 396 ([M + H]⁺) EIHR-MS calcd forC₁₈H₂₀BrClNO₂ [M + H]⁺, 396.0366; found, 396.0355 Compound number 96Name8-Bromo-2-(2-fluorophenethyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.69-2.91 (m, 6H), 2.91-3.05 (m, 2H), 3.63 (s, 2H), (200MHz, CDCl₃) 3.85 (s, 3H), 6.57 (s, 1H), 6.94-7.12 (m, 2H), 7.12-7.33 (m,2H) ¹³C NMR δ 27.2, 29.3, 50.2, 56.2, 56.4, 58.4, 109.1, 110.2, 115.4(50 MHz, CDCl₃) (J = 21.9 Hz), 124.1 (J = 3.2 Hz), 126.5, 127.0, 127.2,128.0 (J = 8.1 Hz), 131.1 (J = 5.0 Hz), 141.2, 145.6, 161.3 (J = 243 Hz)ESI-MS m/z 380 ([M + H]⁺) EIHR-MS calcd for C₁₈H₂₀BrFNO₂ [M + H]⁺,380.0661; found, 380.0662 Compound number 97 Name8-Bromo-6-methoxy-2-(3-(4-nitrophenyl)propyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 1.87-2.06 (m, 2H), 2.49-2.74 (m,4H), 2.74-2.90 (m, (200 MHz, CDCl₃) 4H), 3.53 (s, 2H), 3.85 (s, 3H),6.57 (s, 1H), 7.31-7.43 (m, 2H), 8.07-8.21 (m, 2H) ¹³C NMR δ 28.4, 29.3,33.6, 50.4, 56.2, 56.4, 57.2, 109.0, 110.1, (50 MHz, CDCl₃) 123.8,126.4, 127.2, 129.4, 141.3, 145.6, 146.4, 150.2 ESI-MS m/z 421 ([M +H]⁺) EIHR-MS calcd for C₁₉H₂₂BrN₂O₄ [M + H]⁺, 421.0763; found, 421.0757Compound number 98 Name8-Bromo-6-methoxy-2-(3-(2-nitrophenyl)propyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 1.86-2.11 (m, 2H), 2.51-2.75 (m,4H), 2.75-2.90 (m, (200 MHz, CDCl₃) 2H), 2.90-3.06 (m, 2H), 3.53 (s,2H), 3.83 (s, 3H), 6.55 (s, 1H), 7.31-7.43 (m, 2H), 7.45-7.58 (m, 1H),7.82-7.94 (m, 1H) ¹³C NMR δ 28.1, 29.2, 30.9, 50.1, 56.3, 57.5, 109.1,110.1, 124.8, (50 MHz, CDCl₃) 126.5, 127.1, 127.3, 132.1, 133.0, 137.3,141.2, 145.7, 149.4 ESI-MS m/z 421 ([M + H]⁺) Compound number 101 Name8-(2,4-Dimethoxyphenyl)-6-methoxy-2-(2-(1-naphthyl)ethyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.69-3.02 (m, 6H), 3.19-3.37(m, 4H), 3.73 (s, 3H), (200 MHz, CDCl₃) 3.82-3.93 (m, 6H), 6.54-6.63 (m,1H), 6.63-6.72 (m, 1H), 7.03-7.12 (m, 1H), 7.25-7.29 (m, 1H), 7.29-7.35(m, 1H), 7.35-7.43 (m, 1H), 7.43-7.55 (m, 2H), 7.65-7.76 (m, 1H),7.79-7.89 (m, 1H), 7.95-8.04 (m, 1H) ¹³C NMR δ 29.2, 31.1, 50.7, 54.3,55.5, 55.8, 56.1, 59.2, 99.2, (50 MHz, CDCl₃) 104.9, 110.3, 116.3,122.6, 123.9 (× 2), 125.1, 125.6, 125.7, 126.0, 126.7, 127.0, 128.9,132.0 (× 2), 134.0, 136.6, 141.5, 145.4, 158.2, 160.9 Compound number102 Name 8-(2,4-Dimethoxyphenyl)-2-(2-(3-indolyl)ethyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.72-3.42 (m, 10H), 3.70 (s,3H), 3.85 (s, 3H), (200 MHz, CDCl₃) 3.88 (s, 3H), 6.53-6.70 (m, 2H),6.73-6.87 (m, 1H), 6.94-7.23 (m, 5H), 7.28-7.40 (m, 1H), 7.51-7.69 (m,1H) Compound number 105 Name8-(2,4-Διμετη∘ξψπηενψλ)-6-μετη∘ξψ-2-(4-νιτρ∘πηενετηψλ)-1,2,3,4-τετραηψδρ∘ισ∘θυιν∘λιν-7-∘λ ¹H NMR δ 2.61-2.81 (m,4H), 2.82-2.95 (m, 4H), 3.23 (s, 2H), (200 MHz, CDCl₃) 3.72 (s, 3H),3.85 (s, 3H), 3.88 (s, 3H), 6.53-6.61 (m, 2H), 6.63 (s, 1H), 6.91-7.17(m, 1H), 7.25-7.35 (m, 2H), 8.05-8.13 (m, 2H) ¹³C NMR δ 29.3, 33.7,50.7, 54.2, 55.5, 55.7, 56.0, 59.1, 99.2, (50 MHz, CDCl₃) 104.8, 110.2,116.3, 122.4, 123.7, 125.0, 126.4, 129.6, 131.9, 141.4, 145.2, 146.5,148.6, 158.1, 160.8 EIHR-MS calcd for C₂₆H₂₉N₂O₆ [M + H]⁺, 465.2025;found, 465.2055 Compound number 106 Name2-(4-Chlorophenethyl)-8-(2,4-dimethoxyphenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.47-2.77 (m, 6H), 2.77-2.88(m, 2H), 3.16 (s, 2H), (200 MHz, CDCl₃) 3.65 (s, 3H), 3.78 (s, 3H), 3.80(s, 3H), 6.47-6.54 (m, 2H), 6.55 (s, 1H), 6.93-7.05 (m, 3H), 7.09-7.20(m, 2H) ¹³C NMR δ 29.3, 33.3, 50.6, 54.2, 55.4, 55.7, 56.0, 59.8, 99.2,(50 MHz, CDCl₃) 104.8, 110.2, 116.3, 122.5, 125.1, 126.6, 128.5, 130.1,131.7, 131.9, 139.0, 141.4, 145.2, 158.1, 160.7 ESI-MS m/z 452 ([M −H]⁺), 476 ([M + Na]⁺) EIHR-MS calcd for C₂₆H₂₇ClNO₄ [M − H⁺], 452.1629;found, 452.1623 Compound number 107 Name2-(2,4-Dichlorophenethyl)-8-(2,4-dimethoxyphenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.54-2.65 (m, 2H),2.69-2.95 (m, 6H), 3.26 (s, 2H), (200 MHz, CDCl₃) 3.73 (s, 3H), 3.85 (s,3H), 3.88 (s, 3H), 6.54-6.61 (m, 2H), 6.63 (s, 1H), 7.02-7.07 (m, 1H),7.12 (s, 1H), 7.12 (s, 1H), 7.30-7.33 (m, 1H) ESI-MS m/z 488 ([M + H]⁺)EIHR-MS calcd for C₂₆H₂₆Cl₂NO₄ [M − H]⁺, 486.1239; found, 486.1233Compound number 108 Name2-(4-Bromophenethyl)-8-(2,4-dimethoxyphenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.53-2.83 (m, 6H), 2.84-2.96(m, 2H), 3.23 (bd, 2H), (200 MHz, CDCl₃) 3.72 (s, 3H), 3.85 (s, 3H),3.87 (s, 3H), 6.53-6.62 (m, 2H), 6.62 (s, 1H), 6.98-7.07 (m, 3H),7.28-7.42 (m, 2H) ¹³C NMR δ 29.3, 33.4, 50.6, 54.2, 55.5, 55.7, 56.0,59.7, 99.2, (50 MHz, CDCl₃) 104.8, 110.2, 116.3, 119.8, 122.5, 125.1,126.6, 130.6, 131.4, 131.9, 139.6, 141.4, 145.3, 158.2, 160.8 ESI-MS m/z496 ([M − H]⁺) EIHR-MS calcd for C₂₆H₂₇BrNO₄ [M − H]⁺, 496.1123; found,496.1118 Compound number 109 Name2-(3-Bromophenethyl)-8-(2,4-dimethoxyphenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.54-2.83 (m, 6H), 2.83-2.96(m, 2H), 3.13-3.33 (m, (200 MHz, CDCl₃) 2H), 3.72 (s, 3H), 3.85 (s, 3H),3.87 (s, 3H), 6.54-6.61 (m, 2H), 6.62 (s, 1H), 6.99-7.15 (m, 3H),7.24-7.35 (m, 1H) ¹³C NMR δ 29.2, 33.6, 50.6, 54.2, 55.4, 55.7, 56.0,59.6, 99.2, (50 MHz, CDCl₃) 110.2, 116.3, 122.4, 122.5, 125.0, 126.5,127.5, 129.1, 130.7, 131.7, 131.9, 141.4, 142.9, 145.2, 158.1, 160.8ESI-MS m/z 498 ([M + H]⁺) EIHR-MS calcd for C₂₆H₂₇BrNO₄ [M − H]⁺,496.1123; found, 496.1118 Compound number 110 Name8-(2,4-Dimethoxyphenyl)-6-methoxy-2-(3-methoxyphenethyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.51-2.85 (m, 6H), 2.86-2.98(m, 2H), 3.25 (s, 2H), (200 MHz, CDCl₃) 3.71 (s, 3H), 3.76 (s, 3H), 3.84(s, 3H), 3.86 (s, 3H), 6.53-6.60 (m, 2H), 6.62 (s, 1H), 6.67-6.79 (m,3H), 7.00-7.07 (m, 1H), 7.10-7.21 (m, 1H) ¹³C NMR δ 29.2, 33.9, 50.5,54.1, 55.2, 55.4, 55.6, 55.9, 59.9, (50 MHz, CDCl₃) 99.1, 104.8, 110.1,111.3, 114.4, 116.3, 121.1, 122.4, 125.0, 126.5, 129.3, 131.8, 141.3,142.0, 145.2, 158.0, 159.6, 160.7 ESI-MS m/z 448 ([M − H]⁺), 472 ([M +Na]⁺) EIHR-MS calcd for C₂₇H₃₁NO₅ [M]⁺, 449.2202; found, 449.2197Compound number 111 Name8-(2,4-Dimethoxyphenyl)-2-heptyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 0.83-0.89 (m, 3H), 1.10-1.39 (m, 8H), 1.40-1.45 (m, (200MHz, CDCl₃) 2H), 2.31-2.38 (m, 2H), 2.63-2.71 (m, 2H), 2.85-2.91 (m,2H), 3.16 (s, 2H), 3.73 (s, 3H), 3.86 (s, 3H), 3.87 (s, 3H), 5.30 (s,1H), 6.46-6.61 (m, 2H), 6.67 (d, J = 8.4 Hz, 1H), 7.02-7.06 (m, 1H) ¹³CNMR δ 14.2, 22.8, 27.3, 27.7, 29.4, 32.0, 50.5, 54.5, 55.5, (50 MHz,CDCl₃) 55.7, 56.0, 58.5, 99.2, 104.8, 110.2, 125.3, 132.0, 141.3, 145.1,158.2, 160.8 ESI-MS m/z 414.3 ([M + H]⁺) Compound number 112 Name8-(2,4-Dimethoxyphenyl)-6-methoxy-2-octyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 0.83-0.89 (m, 3H), 1.10-1.38 (m, 10H), 1.40-1.55 (m, (200MHz, CDCl₃) 2H), 2.31-2.38 (m, 2H), 2.63-2.71 (m, 2H), 2.85-2.91 (m,2H), 3.16 (s, 2H), 3.73 (s, 3H), 3.86 (s, 3H), 3.87 (s, 3H), 5.30 (s,1H), 6.55-6.61 (m, 2H), 6.67 (d, J = 8.4 Hz, 1H), 7.02-7.06 (m, 1H) ¹³CNMR δ 14.2, 22.8, 27.2, 27.7, 29.4 (× 2), 29.6, 31.9, 50.5, (50 MHz,CDCl₃) 54.4, 55.5, 55.7, 56.0, 58.4, 99.2, 104.8, 110.2, 125.3, 126.9,132.0, 141.4, 145.2, 158.2 ESI-MS m/s 428.3 ([M + H]⁺) Compound number113 Name8-(2,4-Dimethoxyphenyl)-6-methoxy-2-nonyl-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 0.84-0.90 (m, 3H), 1.24 (bs, 12H), 1.40-1.55 (m, 2H), (200MHz, CDCl₃) 2.31-2.38 (m, 2H), 2.61-2.71 (m, 2H), 2.85-2.91 (m, 2H),3.16 (s, 2H), 3.73 (s, 3H), 3.86 (s, 3H), 3.87 (s, 3H), 5.29 (s, 1H),6.55-6.61 (m, 2H), 6.67 (d, J = 8.4 Hz, 1H), 7.02-7.06 (m, 1H) ¹³C NMR δ14.2, 22.8, 27.2, 27.7, 29.4, 29.7, 32.0, 50.5, 54.5, (50 MHz, CDCl₃)55.5, 55.7, 56.0, 58.4, 99.2, 104.8, 110.2, 122.5, 125.3, 127.0, 131.9,141.4, 145.2, 158.2, 160.7 ESI-MS m/z 442.3 ([M + H]⁺) Compound number114 Name 2-(3,4-Dimethoxyphenethyl)-8-(2,4-dimethoxyphenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.54-2.84 (m, 6H),2.85-2.97 (m, 2H), 3.26 (bd, 2H), (200 MHz, CDCl₃) 3.71 (s, 3H), 3.83(s, 3H), 3.83 (s, 6H), 3.86 (s, 3H), 6.53-6.60 (m, 2H), 6.62 (s, 1H),6.65-6.79 (m, 3H), 7.00-7.07 (m, 1H) ¹³C NMR δ 29.2, 33.5, 50.5, 54.1,55.3, 55.6, 55.8, 55.9, 60.1, (50 MHz, CDCl₃) 99.0, 104.7, 110.1, 111.1,111.9, 116.3, 120.5, 122.4, 125.0, 126.5, 131.8, 133.0, 141.3, 145.1,147.2, 148.7, 158.0, 160.6 ESI-MS m/z 478 ([M − H]⁺), 502 ([M + Na]⁺)EIHR-MS calcd for C₂₈H₃₃NO₆ [M]⁺, 479.2308; found, 479.2302 Compoundnumber 115 Name 2-(2-Chlorophenethyl)-8-(2,4-dimethoxyphenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.48-2.60 (m, 2H), 2.63-2.93(m, 6H), 3.20 (s, 2H), (200 MHz, CDCl₃) 3.63 (s, 3H), 3.75 (s, 3H), 3.77(s, 3H), 6.44-6.52 (m, 2H), 6.54 (s, 1H), 6.92-7.14 (m, 4H), 7.15-7.25(m, 1H) ¹³C NMR δ 29.2, 31.5, 50.4, 54.2, 55.4, 55.6, 55.9, 57.9, 99.1,(50 MHz, CDCl₃) 104.7, 110.1, 116.3, 122.5, 125.0, 126.7, 126.8, 127.5,129.4, 130.8, 131.9, 134.0, 138.0, 141.4, 145.2, 158.1, 160.7 EIHR-MScalcd for C₂₆H₂₉ClNO₄ [M + H]⁺, 454.1785; found, 454.1799 Compoundnumber 116 Name 8-(2,4-Dimethoxyphenyl)-2-(2-fluorophenethyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.55-2.95 (m, 8H), 3.26 (s,2H), 3.72 (s, 3H), 3.84 (s, (200 MHz, CDCl₃) 3H), 3.87 (s, 3H),6.53-6.61 (m, 2H), 6.62 (s, 1H), 6.89-7.22 (m, 5H) ¹³C NMR δ 27.1, 29.2,50.4, 54.2, 55.4, 55.7, 56.0, 58.3, 99.2, (50 MHz, CDCl₃) 104.8, 110.2,115.2 (J = 22.0 Hz), 116.3, 122.5, 124.0 (J = 3.0 Hz), 125.1, 126.7,127.3 (J = 16.0 Hz), 127.8 (J = 7.9 Hz), 131.0 (J = 4.9 Hz), 131.9,141.3, 145.2, 158.1, 160.8, 161.2 (J = 243 Hz) EIHR-MS calcd forC₂₆H₂₉FNO₄ [M + H]⁺, 438.2081; found, 438.2099 Compound number 119 Name8-(2,4-Dimethoxyphenyl)-2-(4-fluorophenethyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.54-2.82 (m, 6H), 2.85-2.96(m, 2H), 3.24 (d, J = 2.1 Hz, (200 MHz, CDCl₃) 2H), 3.71 (s, 3H), 3.84(s, 3H), 3.86 (s, 3H), 6.53-6.60 (m, 2H), 6.62 (s, 1H), 6.84-6.97 (m,2H), 7.00-7.14 (m, 3H) ¹³C NMR δ 29.3, 33.3, 50.7, 54.3, 55.5, 55.8,56.1, 60.1, 99.3, (50 MHz, CDCl₃) 104.9, 110.3, 115.0, 115.4, 116.4,122.7, 125.1, 126.6, 130.1, 130.3, 132.0, 136.2, 141.6, 145.4, 158.2,160.9, 161.5 (d, J = 242 Hz) Compound number 120 Name8-(2,4-Dimethoxyphenyl)-6-methoxy-2-(4-methoxyphenethyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.54-2.80 (m, 6H), 2.84-2.93(m, 2H), 3.25 (s, 2H), (200 MHz, CDCl₃) 3.71 (s, 3H), 3.76 (s, 3H), 3.84(s, 3H), 3.87 (s, 3H), 6.54-6.60 (m, 2H), 6.62 (s, 1H), 6.75-6.83 (m,2H), 7.01-7.11 (m, 3H) ¹³C NMR δ 29.3, 33.1, 50.6, 54.2, 55.3, 55.4,55.7, 56.0, 60.4, (50 MHz, CDCl₃) 99.1, 104.8, 110.2, 113.8, 116.4,122.5, 125.1, 126.7, 129.6, 131.9, 132.6, 141.4, 145.2, 157.9, 158.1,160.7 ESI-MS m/z 448 ([M − H]⁺), 472 ([M + Na]⁺) EIHR-MS calcd forC₂₇H₃₁NO₅ [M]⁺, 448.2124; found, 448.2118 Compound number 121 Name8-(2,4-Dimethoxyphenyl)-6-methoxy-2-(4-methylphenethyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.29 (s, 3H), 2.55-2.84 (m,6H), 2.84-2.96 (m, 2H), (200 MHz, CDCl₃) 3.25 (bd, 2H), 3.71 (s, 3H),3.84 (s, 3H), 3.86 (s, 3H), 6.54-6.60 (m, 2H), 6.62 (s, 1H), 7.01 (s,1H), 7.02-7.07 (m, 4H) ¹³C NMR δ 21.1, 29.3, 33.5, 50.6, 54.2, 55.4,55.7, 56.0, 60.2, (50 MHz, CDCl₃) 99.1, 104.8, 110.2, 116.4, 122.5,125.1, 126.7, 128.6, 129.0, 131.9, 135.5, 137.4, 141.4, 145.2, 158.1,160.7 EIHR-MS calcd for C₂₇H₃₂NO₄ [M + H]⁺, 434.2331; found, 434.2348Compound number 122 Name2-(3-Chlorophenethyl)-8-(2,4-dimethoxyphenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.58-2.99 (m, 8H), 3.12 (d,J = 15.4 Hz, 1H), 3.20 (d, (200 MHz, CDCl₃) J = 15.3 Hz, 1H), 3.65 (s,3H), 3.78 (s, 3H), 3.80 (s, 3H), 6.46-6.54 (m, 2H), 6.55 (s, 1H),6.91-7.01 (m, 2H), 7.03-7.14 (m, 3H) ¹³C NMR δ 29.2, 33.7, 50.6, 54.2,55.4, 55.7, 56.0, 59.6, 99.2, (50 MHz, CDCl₃) 104.8, 110.1, 116.3,122.5, 125.0, 126.2, 126.5, 127.0, 128.8, 129.6, 131.9, 134.1, 141.4,142.5, 145.2, 158.1, 160.8 EIHR-MS calcd for C₂₆H₂₉ClNO₄ [M + H]⁺,454.1785; found, 454.1798 Compound number 123 Name8-(2,4-Dimethoxyphenyl)-6-methoxy-2-(2-methoxyphenethyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 2.52-2.86 (m, 6H), 2.87-2.98(m, 2H), 3.27 (s, 2H), (200 MHz, CDCl₃) 3.71 (s, 3H), 3.75 (s, 3H), 3.83(s, 3H), 3.86 (s, 3H), 6.53-6.61 (m, 2H), 6.62 (s, 1H), 6.76-6.89 (m,2H), 7.01-7.19 (m, 3H) ¹³C NMR δ 28.1, 29.3, 50.3, 54.2, 55.2, 55.4,55.6, 58.3, 99.1, (50 MHz, CDCl₃) 104.7, 104.7, 110.1, 110.3, 116.4,120.4, 122.5, 125.2, 126.9, 127.3, 128.8, 130.2, 131.9, 141.3, 145.1,157.5, 158.1, 160.7 EIHR-MS calcd for C₂₇H₃₂NO₅ [M + H]⁺, 450.2280;found, 450.2297 Compound number 125 Name8-(2,4-Dimethoxyphenyl)-6-methoxy-2-(3-phenylpropyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 1.70-1.88 (m, 2H), 2.35-2.47(m, 2H), 2.53-2.74 (m, (200 MHz, CDCl₃) 4H), 2.83-2.93 (m, 2H), 3.14 (d,J = 15.2 Hz, 1H), 3.23 (d, J = 15.2 Hz, 1H), 3.71 (s, 3H), 3.85 (s, 3H),3.86 (s, 3H), 5.33 (s, 1H), 6.54-6.60 (m, 2H), 6.61 (s, 1H), 7.00-7.06(m, 1H), 7.10-7.20 (m, 3H), 7.21-7.31 (m, 2H) ¹³C NMR δ 28.7, 29.2,33.7, 50.5, 54.2, 55.4, 55.7, 56.0, 57.5, (50 MHz, CDCl₃) 99.1, 104.7,110.3, 116.3, 122.5, 125.3, 127.0, 128.2, 129.3, 132.0, 138.6, 141.4,145.2, 158.1, 160.8 EIHR-MS calcd for C₂₇H₃₂NO₄ [M + H]⁺, 434.2331;found, 434.2356 Compound number 141 Name6-Methoxy-8-(2-methoxyphenyl)-2-(3-(4-nitrophenyl)propyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 1.69-1.90 (m, 2H), 2.29-2.45(m, 2H), 2.60-2.78 (m, (200 MHz, CDCl₃) 4H), 2.83-2.96 (m. 2H), 3.11 (d,J = 15.2 Hz, 1H), 3.19 (d, J = 15.2 Hz, 1H), 3.75 (s, 3H), 3.88 (s, 3H),5.37 (bs, 1H), 6.64 (s, 1H), 6.96-7.09 (m, 2H), 7.14 (dd, J = 7.3, 1.9Hz, 1H), 7.22-7.32 (m, 2H), 7.32-7.43 (m, 1H), 8.05-8.16 (m, 2H) ¹³C NMRδ 28.4, 29.4, 33.5, 50.6, 54.2, 55.8, 56.0, 57.0, 110.3, (50 MHz, CDCl₃)111.4, 121.0, 122.7, 123.7, 124.2, 125.2, 126.2, 129.3, 131.6, 141.2,145.2, 146.4, 150.4, 157.1 ESI-MS m/z 449 ([M + H]⁺) EIHR-MS calcd forC₂₆H₂₉N₂O₅ [M + H]⁺, 449.2076; found, 449.2087 Compound number 142 Name6-Methoxy-8-(2-methoxyphenyl)-2-(3-(2-nitrophenyl)propyl)-1,2,3,4-tetrahydroisoquinolin-7-ol ¹H NMR δ 1.69-1.90 (m, 2H), 2.34-2.51(m, 2H), 2.60-2.78 (m, (200 MHz, CDCl₃) 2H), 2.78-2.99 (m. 4H), 3.13 (d,J = 15.2 Hz, 1H), 3.23 (d, J = 15.2 Hz, 1H), 3.76 (s, 3H), 3.88 (s, 3H),6.64 (s, 1H), 6.96-7.10 (m, 2H), 7.15 (dd, J = 7.3, 1.9 Hz, 1H),7.24-7.29 (m, 1H), 7.32-7.40 (m, 1H), 7.61-7.76 (m, 2H), 7.82-7.92 (m,1H) ¹³C NMR δ 28.1, 29.3, 30.8, 50.2, 54.3, 55.7, 56.0, 57.3, 110.3, (50MHz, CDCl₃) 111.4, 120.9, 122.8, 124.1, 124.7, 125.4, 126.3, 127.0,129.4, 131.6, 132.1, 132.9, 137.4, 141.1, 145.2, 149.4, 157.1 ESI-MS m/z449 ([M + H]⁺) EIHR-MS calcd for C₂₆H₂₉N₂O₅ [M + H]⁺, 449.2076; found,449.2098 Compound number 150 Name8-Bromo-6,7-dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline ¹H NMRδ 2.71-2.94 (m, 8H), 3.63 (s, 2H), 3.82 (s, 3H), 3.83 (s, (200 MHz,CDCl₃) 3H), 6.63 (s, 1H), 7.20-7.31 (m, 5H) ¹³C NMR δ 29.7, 34.1, 50.2,56.1, 56.4, 60.2, 60.6, 111.7, 118.2, (50 MHz, CDCl₃) 126.2, 126.8,128.5, 128.8, 131.9, 140.4, 144.6, 151.7 ESI-MS m/z 376 ([M + H]⁺), 398([M + Na]⁺) EIHR-MS calcd for C₁₉H₂₃BrNO₂ [M + H]⁺, 376.0912; found,376.0905 Compound number 152 Name8-Bromo-6,7-dimethoxy-2-(4-nitrophenethyl)-1,2,3,4-tetrahydroisoquinoline¹H NMR δ 2.69-2.80 (m, 2H), 2.80-2.93 (m, 4H), 2.96-3.10 (m, (200 MHz,CDCl₃) 2H), 3.61 (s, 2H), 3.82 (s, 3H), 3.84 (s, 3H), 6.64 (s, 1H),7.36-7.46 (m, 2H), 8.10-8.19 (m, 2H) ¹³C NMR δ 29.6, 33.9, 50.2, 56.2,56.3, 59.1, 60.6, 111.7, 118.2, (50 MHz, CDCl₃) 123.8, 126.5, 129.7,131.8, 144.7, 146.6, 148.4, 151.8 ESI-MS m/z 421 ([M + H]⁺), 443 ([M +Na]⁺) EIHR-MS calcd for C₁₉H₂₂BrN₂O₄ [M + H]⁺, 421.0763; found, 421.0730Compound number 153 Name8-Bromo-2-(2-chlorophenethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ¹H NMR δ 2.73-2.95 (m, 6H), 2.99-3.13 (m, 2H),3.66 (s, 2H), (200 MHz, CDCl₃) 3.82 (s, 3H), 3.84 (s, 3H), 6.64 (s, 1H),7.10-7.25 (m, 2H), 7.29-7.39 (m, 2H) ¹³C NMR δ 29.7, 31.7, 50.0, 56.2,56.4, 58.0, 60.6, 111.8, 118.3, (50 MHz, CDCl₃) 126.9, 127.0, 127.8,129.6, 131.0, 131.9, 134.2, 138.0, 144.6, 151.7 ESI-MS m/z 410 ([M +H]⁺) EIHR-MS calcd for C₁₉H₂₂BrClNO₂ [M + H]⁺, 410.0522; found, 410.0494Compound number 154 Name8-Bromo-2-(2-fluorophenethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ¹H NMR δ 2.69-2.90 (m. 6H), 2.90-3.04 (m, 2H),3.63 (s, 2H), (200 MHz, CDCl₃) 3.82 (s, 3H), 3.84 (s, 3H), 6.63 (s, 1H),6.95-7.12 (m, 2H), 7.12-7.33 (m, 2H) ¹³C NMR δ 27.3, 29.7, 50.0, 56.2,56.4, 58.4, 60.6, 111.7, 115.3 (J = 22.0 Hz), (50 MHz, CDCl₃) 118.2,124.2, 126.8, 127.1 (J = 16.1 Hz), 127.9 (J = 8.0 Hz), 131.1 (J = 4.8Hz), 131.9, 144.6, 151.6, 161.3 (J = 243 Hz) ESI-MS m/z 394 ([M + H]⁺)EIHR-MS calcd for C₁₉H₂₂BrFNO₂ [M + H]⁺, 394.0818; found, 394.0806Compound number 157 Name8-(2-Fluorophenyl)-6,7-dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline ¹H NMR δ 2.54-2.88 (m, 6H), 2.88-3.05 (m, 2H),3.19 (d, J = 15.0 Hz, (200 MHz, CDCl₃) 1H), 3.30 (d, J = 15.0 Hz, 1H),3.56 (s, 3H), 3.86 (s, 3H), 6.73 (s, 1H), 7.03-7.41 (m, 9H) ¹³C NMR δ29.5, 34.0, 50.3, 54.2, 55.9, 60.0, 60.8, 112.5, (50 MHz, CDCl₃) 115.6(J = 22.2 Hz), 123.6, 124.0 (J = 3.2 Hz), 126.1, 128.1, 128.4, 128.7,129.4, 130.1, 131.8 (J = 3.5 Hz), 140.4, 145.2, 151.0, 159.9 (J = 234Hz) ESI-MS m/z 392 ([M + H]⁺) EIHR-MS calcd for C₂₅H₂₇FNO₂ [M + H]⁺,390.2026; found, 390.2014 Compound number 158 Name8-(2-Chlorophenyl)-6,7-dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline ¹H NMR δ 2.55-2.68 (m, 2H), 2.68-2.89 (m. 4H),2.89-3.00 (m, (200 MHz, CDCl₃) 2H), 3.17 (s, 2H), 3.58 (s, 3H), 3.87 (s,3H), 6.73 (s, 1H), 7.10-7.27 (m, 6H), 7.27-7.36 (m, 2H), 7.43-7.53 (m,1H) ¹³C NMR δ 29.5, 34.0, 50.4, 53.9, 55.9, 60.0, 60.7, 112.3, 125.7,(50 MHz, CDCl₃) 126.1, 126.8, 128.4, 128.8, 129.0, 129.5, 130.1, 131.3,131.8, 133.8, 135.6, 140.4, 144.6, 151.0 ESI-MS m/z 408 ([M + H]⁺)EIHR-MS calcd for C₂₅H₂₇ClNO₂ [M + H]⁺, 408.1730; found, 408.1730Compound number 159 Name6,7-Dimethoxy-8-(2-methoxyphenyl)-2-phenethyl-1,2,3,4-tetrahydroisoquinoline ¹H NMR δ 2.54-2.87 (m, 6H), 2.87-3.00 (m. 2H),3.15 (d, J = 15.1 Hz, (200 MHz, CDCl₃) 1H), 3.26 (d, J = 15.1 Hz, 1H),3.52 (s, 3H), 3.74 (s, 3H), 3.86 (s, 3H), 6.69 (s, 1H), 6.92-7.05 (m,2H), 7.06-7.15 (m, 2H), 7.15-7.29 (m, 4H), 7.29-7.40 (m, 1H) ¹³C NMR δ29.6, 34.0, 50.4, 54.1, 55.5, 55.8, 60.1, 60.6, 110.8, (50 MHz, CDCl₃)111.8, 120.6, 125.2, 126.1, 126.3, 128.4, 128.8, 128.9, 129.6, 131.2,140.5, 145.0, 151.0, 156.9 ESI-MS m/z 404 ([M + H]⁺) EIHR-MS calcd forC₂₆H₃₀NO₃ [M + H]⁺, 404.2226; found, 404.2217 Compound number 165 Name2-(2-Fluorophenethyl)-8-(2-fluorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ¹H NMR δ 2.56-2.68 (m, 2H), 2.68-2.88 (m,4H), 2.88-3.01 (m. (200 MHz, CDCl₃) 2H), 3.20 (d, J = 15.1 Hz, 1H), 3.31(d, J = 15.1 Hz, 1H), 3.56 (s, 3H), 3.86 (s, 3H), 6.73 (s, 1H),6.89-7.06 (m, 2H), 7.09-7.24 (m, 5H), 7.28-7.42 (m, 1H) ¹³C NMR δ 27.2,29.5, 50.1, 54.2, 55.9, 58.2, 60.8, 112.6,, (50 MHz, CDCl₃) 115.3 (J =21.7 Hz), 115.6 (J = 22.0 Hz), 123.6, 124.0 (J = 3.2 Hz), 126.1, 127.2(J = 15.9 Hz), 127.8 (J = 7.9 Hz), 128.1, 129.5 (J = 7.9 Hz), 130.2,131.0 (J = 4.9 Hz), 131.8 (J = 3.0 Hz), 145.2, 151.1, 159.9 (J = 244Hz), 161.2 (J = 243 Hz) ESI-MS m/z 410 ([M + H]⁺) EIHR-MS calcd forC₂₅H₂₆F₂NO₂ [M + H]⁺, 410.1932; found, 410.1927 Compound number 166 Name8-(2-Chlorophenyl)-2-(2-fluorophenethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ¹H NMR δ 2.55-2.68 (m, 2H), 2.68-2.88 (m,4H), 2.88-3.00 (m. (200 MHz, CDCl₃) 2H), 3.18 (s, 2H), 3.57 (s, 3H),3.87 (s, 3H), 6.73 (s, 1H), 6.88-7.05 (m, 2H), 7.06-7.24 (m, 3H),7.26-7.36 (m, 2H), 7.42-7.52 (m, 1H) ¹³C NMR δ 27.2, 29.4, 50.1, 53.9,55.9, 58.1, 60.7, 112.4, (50 MHz, CDCl₃) 115.3 (J = 22.0 Hz), 124.0 (J =3.2 Hz), 125.6, 126.8, 127.2 (J = 16.0 Hz), 127.8 (J = 7.9 Hz), 129.0,129.5, 130.1, 131.0 (J = 4.9 Hz), 131.3, 131.8, 133.8, 135.6, 144.7,151.0, 161.2 (J = 243 Hz) ESI-MS m/z 426 ([M + H]⁺) EIHR-MS calcd forC₂₅H₂₆ClFNO₂ [M + H]⁺, 426.1636; found, 426.1634 Compound number 167Name 2-(2-Chlorophenethyl)-8-(2-fluorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ¹H NMR δ 2.55-2.70 (m, 2H), 2.70-3.02 (m,6H), 3.22 (d, J = 15.1 Hz, (200 MHz, CDCl₃) 1H), 3.32 (d, J = 15.1 Hz,1H), 3.56 (s, 3H), 3.87 (s, 3H), 6.73 (s, 1H), 7.04-7.24 (m, 6H),7.24-7.42 (m, 2H) ¹³C NMR δ 29.5, 31.5, 50.1, 54.3, 55.9, 57.9, 60.8,112.5, (50 MHz, CDCl₃) 115.6 (J = 22.1 Hz), 123.6, 124.1, 126.1, 126.9,127.6, 128.1, 129.4 (J = 7.1 Hz), 129.5, 130.1, 130.9, 131.9, 134.0,137.9, 145.2, 151.1, 159.9 (J = 243 Hz) ESI-MS m/z 426 ([M + H]⁺)EIHR-MS calcd for C₂₅H₂₆ClFNO₂ [M + H]⁺, 426.1636; found, 426.1640Compound number 168 Name2-(2-Chlorophenethyl)-8-(2-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ¹H NMR δ 2.53-2.69 (m, 2H), 2.69-3.03 (m,6H), 3.20 (s, 2H), (200 MHz, CDCl₃) 3.57 (s, 3H), 3.87 (s, 3H), 6.73 (s,1H), 7.02-7.23 (m, 4H), 7.23-7.38 (m, 3H), 7.42-7.54 (m, 1H) ¹³C NMR δ29.5, 31.6, 50.2, 54.0, 55.9, 57.9, 60.7, 112.4, 125.7, (50 MHz, CDCl₃)126.8, 127.6, 129.0, 129.5, 130.1, 130.9, 131.3, 131.8, 133.8, 134.1,135.7, 138.0, 144.7, 151.0 ESI-MS m/z 442 ([M + H]⁺) EIHR-MS calcd forC₂₅H₂₆Cl₂NO₂ [M + H]⁺, 442.1341; found, 442.1335 Compound number 171Name 8-(2-Fluorophenyl)-6,7-dimethoxy-2-(4-nitrophenethyl)-1,2,3,4-tetrahydroisoquinoline ¹H NMR δ 2.62-3.00 (m, 8H), 3.20 (dd, J =17.9, 15.1 Hz, 2H), (200 MHz, CDCl₃) 3.55 (s, 3H), 3.87 (s, 3H), 6.73(s, 1H), 7.07-7.24 (m, 3H), 7.25-7.42 (m, 3H), 8.04-8.15 (m, 2H) ¹³C NMRδ 29.6, 34.1, 50.5, 54.2, 55.9, 59.0, 60.8, 112.5, (50 MHz, CDCl₃) 115.7(J = 22.3 Hz), 123.5, 123.7 (J = 17.4 Hz), 124.0, 125.8, 128.1, 129.5 (J= 7.3 Hz), 129.6, 130.0, 131.8 (J = 3.1 Hz), 145.3, 151.0, 161.2 (J =243 Hz ESI-MS m/z 437 ([M + H]⁺) EIHR-MS calcd for C₂₅H₂₆FN₂O₄ [M + H]⁺,437.1877; found, 437.1874 Compound number 172 Name8-(2-Chlorophenyl)-6,7-dimethoxy-2-(4-nitrophenethyl)-1,2,3,4-tetrahydroisoquinolinee ¹H NMR δ 2.61-2.99 (m, 8H), 3.13 (dd, J= 16.6, 15.2 Hz, 2H), (200 MHz, CDCl₃) 3.57 (s, 3H), 3.87 (s, 3H), 6.73(s, 1H), 7.11-7.22 (m, 2H), 7.24-7.37 (m, 4H), 7.47-7.52 (m, 1H),8.03-8.14 (m, 2H) ¹³C NMR δ 29.5, 34.0, 50.6, 53.9, 58.9, 60.7, 112.3,123.7, 125.3, (50 MHz, CDCl₃) 126.9, 129.0. 129.6, 130.0, 131.3, 131.8,133.7, 135.6, 144.7, 146.5, 148.6, 151.1 ESI-MS m/z 453 ([M + H]⁺)EIHR-MS calcd for C₂₅H₂₆ClN₂O₄ [M + H]⁺, 453.1581; found, 453.1571Compound number 173 Name6,7-Dimethoxy-8-(2-methoxyphenyl)-2-(4-nitrophenethyl)-1,2,3,4-tetrahydroisoquinoline ¹H NMR δ 2.59-3.00 (m, 8H), 3.17 (dd, J =19.8, 15.0 Hz, 2H), (200 MHz, CDCl₃) 3.52 (s, 3H), 3.73 (s, 3H), 3.86(s, 3H), 6.69 (s, 1H), 6.92-7.04 (m, 2H), 7.07 (dd, J = 7.4, 2.2 Hz,1H), 7.26-7.41 (m, 3H), 8.03-8.14 (m, 2H) ¹³C NMR δ 29.6, 34.0, 50.6,54.1, 55.5, 55.9, 59.0, 60.6, 110.8, (50 MHz, CDCl₃) 111.8, 120.6,123.6, 125.1, 126.0, 129.0, 129.6, 131.1, 145.1, 146.5, 148.7, 151.1,156.9 ESI-MS m/z 449 ([M + H]⁺) EIHR-MS calcd for C₂₆H₂₉N₂O₅ [M + H]⁺,449.2076; found, 449.2071

The 5-HT_(2A) Receptor Binding Affinity of Compounds 116, 157 and 167.

The 5-HT_(2A) receptor binding affinity data are represented by K_(i)values. As shown in Table 8, the 5-HT_(2A) receptor binding affinity ofcompounds 116, 157 and 167 are higher than those of the well-known5-HT_(2A) receptor antagonists, sarpogrelate and ketanserin.

TABLE 8 The 5-HT_(2A) receptor binding affinity data The presentinvention Prior-art (compound number) sarpogrelate ketanserin 116 157167 K_(i) (nM) 8.39 3.5 3.47 2.21 0.119

Protective Effects of Post-Treatment of Multiple Doses of Compound 116on LPS Induced Endotoxaemia in Mice Model:

12 hours after intraperitoneal injection of lipopolysaccharide (LPS) 100mg/kg, compound 116 100 μg/kg or 300 μg/kg were administratedintraperitoneally or subcutaneously every 6 hour till 48 hours after LPSinsults. FIG. 7 shows the result. Both 100 μg/kg and 300 μg/kg treatmentof compound 116 shifted the survive curve rightward significantlycompared to the vehicle control group (p<0.01.). Survival curves werecompared by the Log rank test, and 3 days survival rate was compared bythe chi square test.

Protective Effects of Post-Treatment of Multiple Doses of Compound 167on LPS Induced Endotoxaemia in Mice Model:

The experiment method is the same as described above and FIG. 8 showsthe result.

Compound 116 Did not Exert Platelet Activation, but Inhibited 5-HTInduced Amplification of Platelet Aggregation:

Blood samples were collected from male adult Spraque-Dawley rats, andplatelet rich plasma (PRP) and platelet poor plasma (PPP) were obtainedby centrifugation. Aggregation was elicited by adding collagen 3 μg/mLin PRP, and the aggregation response was recorded as the change of lighttransmission of PRP with Lumi-aggregometer. In FIG. 9 a, collageninduced platelet aggregation, and the aggregation response was amplifiedby adding 10 μM serotonin in 30 seconds before adding collagen, as shownin FIG. 9 b. The amplifying effects of serotonin was blocked by adding10 μM ketanserin or 3 μg/mL compound 116 in 30 seconds before addingserotonin, as shown in FIG. 9 c and FIG. 9 d.

Compound 116 Inhibits Serotonin Induced Rat De-Endothelial ThoracicDescending Aorta Contraction:

Thoracic aortae were obtained from adult male Sprague Dawley rats. Theaortae were cleared of adhering periadventitial fat and cut into strips3-4 mm in length. Later, the relaxation in response to acetylcholine (1μM) following PE (0.1 μM) was considered as evidence that theendothelium was intact. The tissue was incubated with warmed (37° C.),oxygenated (95% O₂/5% CO₂) Krebs-Henseleit solution (KBS, pH7.4)consisting of NaCl 118.2 mM, KCl 4.7 mM, KH₂PO₄ 1.2 mM, MgSO₄ 1.2 mM,CaCl₂·2H₂O 1.9 mM, NaHCO₃ 25 mM and glucose 11.7 mM. Indomethacin (10μM) was added to prevent the production of prostanoids. One end of thesegment was fixed to the organ bath chamber, and the other to a forcetransducer (Type BG 25; Gould, Oxnard, Calif., USA) in which tension isrecorded (model RS 3400 recorder, Gould). The preparations were allowedto equilibrate for at least 60 min under a passive tension of 1.5±0.2 g.Cumulative responses to serotonin (30 nM-0.1 mM) were examined for 20min after addition of 0.03 or 0.1 μM compound 116 to the organ bath.Contraction responses were expressed as the percentage of maximumcontraction. As shown in FIG. 10, compound 116 inhibits serotonininduced smooth muscle contraction in a dose dependent manner.

EMBODIMENTS

-   1. A compound, comprising a formula of:

-   2. A compound as claimed in claim 1, providing an antagonism to a    5-HT_(2A) receptor.-   3. A compound as claimed in claim 1, inhibiting an aorta    contraction.-   4. A compound as claimed in claim 3, wherein the aorta contraction    is induced by a serotonin-   5. A compound as claimed in claim 1, inhibiting a platelet    aggregation.-   6. A compound as claimed in claim 5, wherein the platelet    aggregation is induced by a serotonin-   7. A compound or a pharmaceutically acceptable salt thereof,    comprising a formula of:

-   -   wherein R₁ is one selected from a group consisting of hydrogen,        C₁₋₁₂ linear chain alkyl group, C₁₋₁₂ branched chain alkyl        group, (CH₂)_(n)(Hete)R₁₀R₁₁R₁₂ and (CH₂)_(n)ArR₁₀R₁₁R₁₂,        wherein the n is an integer from 1 to 6, Hete is a heterocyclic        group, and R₁₀, R₁₁ and R₁₂ are independently selected from a        group consisting of hydrogen, halo group, nitro group, amino        group, cyano group, acetyl group, C₁₋₆ linear chain saturated        alkyl group, C₁₋₆ linear chain saturated alkoxy group and C₁₋₆        linear chain saturated haloalkyl group;    -   R₂ is one of a hydrogen and a C₁₋₆ linear chain saturated alkyl        group;    -   R₃ is one of a hydroxyl group and a C₁₋₆ linear chain saturated        alkoxy group;    -   R₄ is one of a hydroxyl group and a C₁₋₆ linear chain saturated        alkoxy group; and    -   X₁, X₂, X₃, X₄ and X₅ are independently selected from a group        consisting of hydrogen, halo group, nitro group, amino group,        cyano group, acetyl group, C₁₋₆ linear chain saturated alkyl        group, C₁₋₆ branched chain saturated alkyl group, C₁₋₆ linear        chain saturated alkoxy group, C₁₋₆ branched chain saturated        alkoxy group, C₁₋₆ linear chain saturated alkylthio group, C₁₋₆        branched chain saturated alkylthio group, C₁₋₆ linear chain        saturated haloalkyl group and C₁₋₆ branched chain saturated        haloalkyl group.

-   8. A compound as claimed in claim 7, wherein the halo group is one    selected from a group consisting of fluorine, chlorine, bromine and    iodine.

-   9. A compound as claimed in claim 7, wherein the heterocyclic group    is one selected from a group consisting of naphthyl group, indolyl    group, isoindolyl group, indazolyl group, benzofuranyl group,    isobenzofuranyl group, benzothiophenyl group, benzimidazolyl group,    benzoxazolyl group and benzothiazolyl group.

-   10. A compound as claimed in claim 7, providing an antagonism to a    5-HT_(2A) receptor.

-   11. A compound as claimed in claim 7, inhibiting an aorta    contraction.

-   12. A compound as claimed in claim 12, wherein the aorta contraction    is induced by a serotonin

-   13. A compound as claimed in claim 7, inhibiting a platelet    aggregation.

-   14. A compound as claimed in claim 13, wherein the platelet    aggregation is induced by a serotonin

-   15. A pharmaceutical composition, comprising:    -   a pharmaceutically acceptable carrier; and    -   a therapeutically effective amount of a compound having a        formula of:

-   -   wherein R₁ is one selected from a group consisting of hydrogen,        C₁₋₁₂ linear chain alkyl group, C₁₋₁₂ branched chain alkyl        group, (CH₂)_(n)(Hete)R₁₀R₁₁R₁₂ and (CH₂)_(n)ArR₁₀R₁₁R₁₂,        wherein the n is an integer from 1 to 6, Hete is a heterocyclic        group, and R₁₀, R₁₁ and R₁₂ are independently selected from a        group consisting of hydrogen, halo group, nitro group, amino        group, cyano group, acetyl group, C₁₋₆ linear chain saturated        alkyl group, C₁₋₆ linear chain saturated alkoxy group and C₁₋₆        linear chain saturated haloalkyl group;    -   R₂ is one of a hydrogen and a C₁₋₆ linear chain saturated alkyl        group;    -   R₃ is one of a hydroxyl group and a C₁₋₆ linear chain saturated        alkoxy group;    -   R₄ is one of a hydroxyl group and a C₁₋₆ linear chain saturated        alkoxy group; and    -   X₁, X₂, X₃, X₄ and X₅ are independently selected from a group        consisting of hydrogen, halo group, nitro group, amino group,        cyano group, acetyl group, C₁₋₆ linear chain saturated alkyl        group, C₁₋₆ branched chain saturated alkyl group, C₁₋₆ linear        chain saturated alkoxy group, C₁₋₆ branched chain saturated        alkoxy group, C₁₋₆ linear chain saturated alkylthio group, C₁₋₆        branched chain saturated alkylthio group, C₁₋₆ linear chain        saturated haloalkyl group and C₁₋₆ branched chain saturated        haloalkyl group.

-   16. A pharmaceutical composition as claimed in claim 15, wherein the    halo group is one selected from a group consisting of fluorine,    chlorine, bromine and iodine.

-   17. A pharmaceutical composition as claimed in claim 15, wherein the    heterocyclic group is one selected from a group consisting of    naphthyl group, indolyl group, isoindolyl group, indazolyl group,    benzofuranyl group, isobenzofuranyl group, benzothiophenyl group,    benzimidazolyl group, benzoxazolyl group and benzothiazolyl group.

-   18. A method of treating a sepsis, comprising a step of    administering to a subject in need thereof an effective amount of    the pharmaceutical composition of claim 15.

1. A compound, comprising a formula of:


2. A compound as claimed in claim 1, providing an antagonism to a5-HT_(2A) receptor.
 3. A compound as claimed in claim 1, inhibiting anaorta contraction.
 4. A compound as claimed in claim 3, wherein theaorta contraction is induced by a serotonin.
 5. A compound as claimed inclaim 1, inhibiting a platelet aggregation.
 6. A compound as claimed inclaim 5, wherein the platelet aggregation is induced by a serotonin. 7.A compound or a pharmaceutically acceptable salt thereof, comprising aformula of:

wherein R₁ is one selected from a group consisting of hydrogen, C₁₋₁₂linear chain alkyl group, C₁₋₁₂ branched chain alkyl group,(CH₂)_(n)(Hete)R₁₀R₁₁R₁₂ and (CH₂)_(n)ArR₁₀R₁₁R₁₂, wherein the n is aninteger from 1 to 6, Hete is a heterocyclic group, and R₁₀, R₁₁ and R₁₂are independently selected from a group consisting of hydrogen, halogroup, nitro group, amino group, cyano group, acetyl group, C₁₋₆ linearchain saturated alkyl group, C₁₋₆ linear chain saturated alkoxy groupand C₁₋₆ linear chain saturated haloalkyl group; R₂ is one of a hydrogenand a C₁₋₆ linear chain saturated alkyl group; R₃ is one of a hydroxylgroup and a C₁₋₆ linear chain saturated alkoxy group; R₄ is one of ahydroxyl group and a C₁₋₆ linear chain saturated alkoxy group; and X₁,X₂, X₃, X₄ and X₅ are independently selected from a group consisting ofhydrogen, halo group, nitro group, amino group, cyano group, acetylgroup, C₁₋₆ linear chain saturated alkyl group, C₁₋₆ branched chainsaturated alkyl group, C₁₋₆ linear chain saturated alkoxy group, C₁₋₆branched chain saturated alkoxy group, C₁₋₆ linear chain saturatedalkylthio group, C₁₋₆ branched chain saturated alkylthio group, C₁₋₆linear chain saturated haloalkyl group and C₁₋₆ branched chain saturatedhaloalkyl group.
 8. A compound as claimed in claim 7, wherein the halogroup is one selected from a group consisting of fluorine, chlorine,bromine and iodine.
 9. A compound as claimed in claim 7, wherein theheterocyclic group is one selected from a group consisting of naphthylgroup, indolyl group, isoindolyl group, indazolyl group, benzofuranylgroup, isobenzofuranyl group, benzothiophenyl group, benzimidazolylgroup, benzoxazolyl group and benzothiazolyl group.
 10. A compound asclaimed in claim 7, providing an antagonism to a 5-HT_(2A) receptor. 11.A compound as claimed in claim 7, inhibiting an aorta contraction.
 12. Acompound as claimed in claim 12, wherein the aorta contraction isinduced by a serotonin.
 13. A compound as claimed in claim 7, inhibitinga platelet aggregation.
 14. A compound as claimed in claim 13, whereinthe platelet aggregation is induced by a serotonin.
 15. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier; and atherapeutically effective amount of a compound having a formula of:

wherein R₁ is one selected from a group consisting of hydrogen, C₁₋₁₂linear chain alkyl group, C₁₋₁₂ branched chain alkyl group,(CH₂)_(n)(Hete)R₁₀R₁₁R₁₂ and (CH₂)_(n)ArR₁₀R₁₁R₁₂, wherein the n is aninteger from 1 to 6, Hete is a heterocyclic group, and R₁₀, R₁₁ and R₁₂are independently selected from a group consisting of hydrogen, halogroup, nitro group, amino group, cyano group, acetyl group, C₁₋₆ linearchain saturated alkyl group, C₁₋₆ linear chain saturated alkoxy groupand C₁₋₆ linear chain saturated haloalkyl group; R₂ is one of a hydrogenand a C₁₋₆ linear chain saturated alkyl group; R₃ is one of a hydroxylgroup and a C₁₋₆ linear chain saturated alkoxy group; R₄ is one of ahydroxyl group and a C₁₋₆ linear chain saturated alkoxy group; and X₁,X₂, X₃, X₄ and X₅ are independently selected from a group consisting ofhydrogen, halo group, nitro group, amino group, cyano group, acetylgroup, C₁₋₆ linear chain saturated alkyl group, C₁₋₆ branched chainsaturated alkyl group, C₁₋₆ linear chain saturated alkoxy group, C₁₋₆branched chain saturated alkoxy group, C₁₋₆ linear chain saturatedalkylthio group, C₁₋₆ branched chain saturated alkylthio group, C₁₋₆linear chain saturated haloalkyl group and C₁₋₆ branched chain saturatedhaloalkyl group.
 16. A pharmaceutical composition as claimed in claim15, wherein the halo group is one selected from a group consisting offluorine, chlorine, bromine and iodine.
 17. A pharmaceutical compositionas claimed in claim 15, wherein the heterocyclic group is one selectedfrom a group consisting of naphthyl group, indolyl group, isoindolylgroup, indazolyl group, benzofuranyl group, isobenzofuranyl group,benzothiophenyl group, benzimidazolyl group, benzoxazolyl group andbenzothiazolyl group.
 18. A method of treating a sepsis, comprising astep of administering to a subject in need thereof an effective amountof the pharmaceutical composition of claim 15.